The story occurs ten years before the events of Liberty, and represents it's antagonist Nicholas Hough as the central character. In this scenario which explores his life of crime, Nicholas plans to secure the "American Dream" for himself by projecting an elaborate coup to become the most powerful gangland kingpin in the fictional city Haughland. His progressive efforts to do so involve creating and establishing his own criminal organization, while other major elements see Nicholas gaining alliances and employment through several crime lords — up to the point where he romances and eventually marries the daughter of an aging Italian mob boss.
The story begins one year after Nicholas Hough, a seasoned criminal, joined his crew of professional bank robbers in doing an armed robbery in Coppa Town. It ended with Nicholas betraying his fellow accomplices and escaping with all the money on his own.
Months later, he arrives in Los Santos to settle his life after getting away with the Coppa Town heist unscathed. He leaves the airport and goes downtown with his criminal contact Lamar Davis, a gangbanger and co-leader of The Families street-gang. They arrive at an apartment owned by Lamar's roommate and drug dealer Gerald, who tasks Nicholas in helping The Families retake their old territory from the rival Ballas and Vagos gang factions. Nicholas accomplishes the task with ease, and earns Gerald's respect to the point where he gets recruited into The Families. He is later introduced to Simeon Yetarian, a xenophobic vehicle salesman and Lamar's employer who hires Nicholas to hijack cars from people in debt to him.
It slowly becomes clear that Nicholas is planning to launch an elaborate gangland coup to secure the "American Dream" for himself, which turns out to be part of his purpose with Los Santos. This commences when he secretly allies with the Ballas and Vagos gangs to disorganize The Families, which eventually comes to fruition after Nicholas stages a lethal confrontation between the three factions that ends with him killing Gerald and causing Lamar to get arrested as the instigator behind the gang war. It is then Nicholas begins to create his own criminal organization, the Blacklist Crime Syndicate, which he subsequently operates in a major region called Haughland.
Nicholas soon comes into contact with Martin Madrazo, a notorious Mexican drug lord whose namesake cartel operate the biggest narcotics ring in Los Santos. This happens after Simeon orders Nicholas to steal a car that belongs to his favourite customer, Natalia Zverovna, who later turns out to be Madrazo's mistress as well. When Madrazo later demands compensation from Simeon under the threat of violence, Nicholas offers to work for Madrazo and he agrees. Madrazo subsequently employs Nicholas as his personal hitman who is often assigned to murder known or suspected witnesses who threaten to testify against the Madrazo Cartel in court. Nicholas quickly earns Madrazo's trust by carrying out his requested assassinations, and is eventually sent to kill millionaire Jerry Kapowitz in Liberty City. Afterwards, he discovers that the reason why Madrazo wanted Kapowitz dead was to steal his diamonds that are worth $2 million. Nicholas also learns that the Liberty City Bravta and other mafia families, including five Cosa Nostra syndicates who each represent "The Commission", have previously been in contention for the diamonds ever since they first came to the city illegally five years ago, which was all before they ultimately came into Kapowitz's possession.
Seeing the diamonds as an opportunity to continue with his own gangland expansions, Nicholas decides not to bring them to Madrazo in lieu of using the diamonds to gain an alliance with all five mafia families of "The Commission". He meets up with Don Giovanni Ancelotti, head of the weakest crime family in "The Commission", and offers him the diamonds in exchange for recruitment into his organization. Giovanni agrees to "welcome" Nicholas in the family business, but only if Nicholas first helps the Ancelottis negotiate a potential collusion with Kenny Petrovic, a powerful Russia crime lord who controls the Liberty City Bravta. This works successfully and Nicholas secures his association with the Ancelottis, along with Petrovic himself. Soon enough, he becomes as the Ancelottis' new underboss after managing to recoup their status as the most powerful family in "The Commission". Nicholas also grows attached to Giovanni's trophy-daughter Gracie, and they soon form a relationship with each other.
When Nicholas returns to Los Santos, he learns that Simeon and Natalia are planning to leave in Gracie's old car so they could escape Madrazo's wrath over their affair. He confronts and kills them at the dealership, then returns the car to Gracie before proposing to her. This further establishes Nicholas' loyalty to the Ancellotis, but at the same time causes Madrazo to terminate his employment as he angrily vows retribution for Natalia's murder. With his ties to Madrazo all but served, Nicholas assembles the Ancelottis to kill him and eliminate his narcotic cartel by laying siege to his mansion. The attack ends with Nicholas executing Madrazo after the Ancelottis have killed all of Madrazo's henchmen, while Madrazo's wife Patricia is the only person to be spared in the resulting gunfight; she leaves with Nicholas and the Ancelottis after they set fire to Madrazo's mansion.
After killing Madrazo and destroying his empire, Nicholas continues to make progress in consolidating his takeover of various black markets in Haughland and other central regions. He also plans to secure his position as the number one drug trafficker by taking control of all cocaine and heroin distributions. To achieve those goals, Nicholas purchases assets in nearly bankrupt companies and ends up renovating them as fronts for his illicit operations. This steadily builds a three-way criminal partnership between Nicholas and his perceived gangland rivals, Tommy Vercetti and Trevor Phillips. At somepoint, Nicholas recruits them along with Irish criminal Packie McReary and his accomplice Gordon Sergant in a series of heist operations. They manage to pull off a number of accomplished bank robberies that involves defrauding the group's business rival Don Percival, and additionally breaking into the prison where Packie's brother Gerry and his narcotrafficking cellmate Elizabeta Torres are both locked up in. Following these events is Nicholas' drug collusion with Elizabeta, and his alliances with the McReary Brothers along with the competitive likes of Gracie's friend and illegitimate nightclub owner Anthony "Gay Tony" Prince; his real estate business partner Yusef Amir; the Angels of Death outlaw motorcycle club president Lester Arnold; the Yardies gang boss Real Badman; and the religious cult leader Cris Formage.
During this time, Nicholas marries Gracie with her father's blessing and the newfound couple proceed to acquire themselves a luxurious and heavily-guarded estate in Haughland. Their marriage continues to thrive for the next four years, but eventually Nicholas begins to distance himself from the Ancelottis in order to continue empowering his own gangland influence. This soon involves two-timing with Gracie's best friend Sharon Morton, who conveniently turns out to be Petrovic's long-lost daughter and later becomes Nicholas' secret mistress. It eventually transpires that Nicholas' affair with Sharon is actually part of his elaborate plan to sabotage the Ancelotti-Petrovic collusion, thus manipulating the two crime families into waging war on each other. Furthermore, Nicholas receives suspicions from both Petrovic and Elizabeta since the pair are each in the midst of a power struggle against Arnold and Badman respectively. At the same time, Nicholas causes a problematic rift between Gracie and her father over her ongoing drug addiction — something that Giovanni disapproves from his daughter. When Gracie continues to ignore her father's demand to end her addiction, she ends up getting hospitalized after suffering a drug overdose. Nicholas visits Gracie just as her father disowns his daughter for ignoring his demands, which sparks increasingly paranoid behaviour for Gracie. She eventually accuses her husband of supporting Giovanni more than her, but Nicholas tells her otherwise and claims to have always loved her. The couple share a miss before Gracie suddenly undergoes a cardiac arrest, and she dies in front of Nicholas.
Prior to Gracie's death, Nicholas authorizes his fence Terry Harvester and fellow acquaintance Wade Johnson to launder all the money he and his crew robbed from their heists. When he later a sting operation during a private meeting with Terry about his money laundering development, Nicholas sets out to eliminate all loose ends to his criminal activities. He first murders both the McReary Brothers and Gordon in retribution for kidnapping Gracie nearly a decade ago. Nicholas then stages a gang war between the Yardies and Angels of Death by luring the two parties to an apparent drug trade. This works successfully as the two gangs wipe each other out in a gunfight, after which Nicholas executes both Arnold and Badman to implicate Elizabeta as the instigator behind the shootout. Later on, Nicholas arranges for Elizabeta to be raped and subsequently murdered in her safehouse. After proceeding to target Formage and Yusef for his next assassinations, Nicholas kills the former at his cult session and supposedly the latter at a public speaking that is being hosted by wealthy father Adbul — whom he ends up killing as well. Trevor and Gay Tony are spared from Nicholas' assassinations in the end, and they separately part ways with Nicholas afterwards.
On the day of Gracie's funeral, Nicholas invites Vercetti and Petrovic to attend. He delivers an eulogy on Gracie, then asks Vercetti to comfort him outside. During a conversation at Gracie's intended grave, Nicholas reveals that he killed her by switching off his wife's life support that caused Gracie's death. He then kills Vercetti, and afterwards the priest once back inside the church. Nicholas fires another gunshot that authorizes his mass security to start killing the other attendees. Petrovic attempts to escape, but Nicholas shoots him dead at the end of the massacre. When Giovanni learns about what Nicholas has been doing, he summons a meeting with other rival leaders of The Commission to discuss taking him out. As the meeting comes to a close, Nicholas suddenly emerges with his Blacklist gunmen. They kill everyone all the mafia bosses, and Nicholas confesses his role behind Gracie's murder to Giovanni before executing him last.
With all his enemies vanquished and the region's criminal underworld fully subjugated to his own influence, Nicholas has officially cemented himself as the undisputed crime kingpin of Haughland — known as "The Criminal Mastermind". In the epilogue, five years later, Nicholas has established a new crime society that serves under his own gangland regime. The final scene features Nicholas learning that his ally Stink Smiths has betrayed his own street-gang, "The Streets", and has lured both his preteen protégé Junior Christ and the latter's father Nicky into a trap. Nicholas, upon recognizing Nicky as his former partner-in-crime from the botched Coppa Town heist at the previous decade, sets out to confront him as the staging events of their conflict in Liberty commence.
- Nicholas Hough — An ambitious master criminal who elaborately establishes himself as the undisputed crime kingpin and the most powerful gangland boss of Haughland; he is also the creator and founder of the Blacklist Crime Syndicate.
- Terry Harvester — A seasoned criminal fence and Nicholas' money launderer who serves as his main gangland contact.
- Gracie Ancelotti — A drug-addicted call girl and Giovanni's daughter who gradually becomes Nicholas' trophy-wife.
- Sharon Morton — A sexaholic prostitute and Gracie's best-friend who slowly turns out to be Petrovic's long-lost daughter; she later becomes Nicholas' secret mistress.
- Yusuf Amir — An influential real estate developer and the major benefactor of Nicholas' crime syndicate.
- Giovanni Ancelotti — An aging Italian mafia boss and Don of the Ancelotti Crime Family who is Gracie's father.
- Kenny Petrovic — A predominant Russian crime lord and founder of the Petrovic Mafyia who controls the Liberty City Bravta.
- Packie McReary — An infamous gangster who is the youngest brother and second-in-command of the McReary family.
- Gerry McReary — A convicted habitual offender who is the eldest brother and leader of the McReary family.
- Elizabeta Torres — An imprisoned narcotrafficker known as "the prison landlady" who is currently the drug queenpin of Liberty City.
- Lamar Davis — An enthusiastic gangbanger and high-ranking member of The Families street gang.
- Gerald — A reclusive drug baron and leader of The Families street gang.
- Simeon Yetarian — A xenophobic vehicle salesman and Lamar's employer.
- Martin Madrazo – An illegitimate Mexican drug lord and founder of the Madrazo Cartel.
- Natalia Zverovna – A striptease everywoman who is Simeon's favourite customer and Madrazo's secret mistress.
- Trevor Phillips – A psychotic arms-dealer and the namesake CEO of Trevor Phillips Enterprises.
- Tommy Vercetti — A legendary crime boss and the number one drug kingpin of Vice City.
- Wade Johnson — A mysterious federal contact who is seemingly affiliated with Terry Harvester.
- Real Badman — A drug-addicted gunman and the frontman of the Yardies' gang.
- Lester Arnold — A ferocious gang lord and the leader of the Angels of Death outlaw motorcycle club.
- Gordon Sergeant — A sociopathic armed robber and longtime member of the McReary Crime Family.
- Sergei — A high-ranking member of the Russian Mafia who used to work for Petrovic's enemies and now serves as his right-hand man.
- Anthony "Gay Tony" Prince — A legitimate nightclub owner and Gracie's business partner.
- Lester Crest — An individualistic cracker and Trevor's old acquaintance.
- Jerry Kapowitz — A wealthy businessman and owner of the illegal diamonds that previously represented high significance with the Liberty City criminal underworld.
- Adbul Amir — A prosperous industrialist and Yusef's estranged father.
- Maria Valvona — A senior crime lady and Don of the Pavano Crime Family who represents one of the five Liberty City Mafia Families called "The Commission".
- Harvey Noto — An elderly mob boss Don of the Messina Crime Family who represents one of the five Liberty City Mafia Families called "The Commission".
- Vincent Lupisella — An ageing mobster and Don of the Lupisella Crime Family who represents one of the five Liberty City Mafia Families called "The Commission".
- Cris Formage — A scandalous cult leader and the founder of the Epsilon Program.
- Don Percival — A global entrepreneur and the supreme head of Merryweather Security Consulting.
- Liberty: The Criminal Mastermind is perfectly compared to 1983 crime film Scarface, with the storyline also acting as a close resemblance to Grand Theft Auto: Vice City.
- Ironically, the story's protagonist villain Nicholas Hough is virtually portrayed like Tony Montana from Scarface and Tommy Vercetti from Grand Theft Auto: Vice City.