In 2013 — five years after escaping the Coppa Town botched heist unscathed — professional criminal Nicholas Hough arrives in Los Santos with the intent of pursuing the American Dream. At the airport, he is collected by his acquaintance Lamar Davis — a local gangbanger — who then takes him to the apartment of his drug dealer: Gerald.
Gerald tasks Nicholas in aiding Lamar and his street-gang — The Families — with their territorial conflict against other gang families, particularly the Families' main rivals; the Ballas. In doing so, Nicholas earns Gerald's respect and is recruited into The Families. He soon begins working for Lamar's crooked employer Simeon Yetarian, and — on one occasion — is introduced to his favourite customer: Natalia Zverovna, the mistress of Mexican drug lord Martin Madrazo. At somepoint, Nicholas is contacted by his money launderer Terry Harvester with a request; to travel to Liberty City and negotiate a deal with both Russian kingpin Kenny Petrović and Italian mob boss Giovanni Ancelotti respectively. This successfully works and Nicholas is officially inducted into both criminal organizations.
Back in Los Santos, Nicholas' coup surreptitiously comes into fruition; he secretly forms an alliance with the Ballas to invoke disorder on The Families, thereby prompting Gerald and Lamar into disrupting a meet-up between the two gangs. Nicholas uses this opportunity to organize a sting operation in the gang meeting, and successfully instigates a gunfight by shooting Gerald — ultimately killing him and framing Lamar for the murder, leading to the latter's leading to the latter's untimely arrest in the process. With The Families' disorganized following Gerald's death and Lamar's arrest, Nicholas openly declares his alliance with the Ballas and other street-gang families to establish his own crime syndicate — the Blacklist crime syndicate.
After assassinating Vice City entrepreneur Jerry Kapowitz — the owner of smuggled diamonds worth $2 million, which the Ancelotti syndicate have formerly been seeking to obtain back five years ago in Liberty City — Nicholas becomes the new Ancelotti consigliere and additionally grows attracted with Giovanni's daughter: Gracie, whose business partner Tony Prince later becomes influential in Nicholas' organization. When Simeon is on the verge of selling Gracie's missing car to Natalia in a business deal, Nicholas personally kills them before delivering the car to Gracie. This further impresses Giovanni, but angers Madrazo — who promptly cuts his ties with Nicholas, vowing retribution for his mistress' death. In response, Nicholas assembles a lethal assault in Madrazo's home and — after setting it on fire — executes him before leaving with his housewife: Patricia.
With all obstacles apparently removed, Nicholas gradually commences his takeover in the criminal underworld and marries Gracie with her father's approval; the two start living together in a vast and luxurious heavily-guarded estate. He also becomes the distributor of Petrović's product and embarks on several partnerships multiple crime bosses — including Vice City's kingpin Tommy Vercetti, Blaine Country's drug lord Trevor Phillips, Liberty City's influential magnate Yusuf Amir, and Los Santos' cultistic baron Cris Formage. Building up on his criminal empire, Nicholas ends up becoming the sole trafficker of various drug operations — specifically both cocaine and heroin.
By 2017, Nicholas and Gracie begin to distance themselves from Giovanni — with the former growing unsatisfied at being a figurehead for the Ancelottis, and the latter disregarding her father's disapproval of her addiction to cocaine. At Terry's suggestion, Nicholas issues a prison breakout to extract notorious convict Elizabeta Torres from custody and recruit her into his drug operation; Elizabeta's former employee Patrick McReary and his recently imprisoned brother Gerald are enrolled into the organization as well. Together with the McReary brothers, Nicholas orchestrates two robberies on behalf of Terry's two associates — the mysterious liaison Wade Johnson and fellow merchant prince Don Percival. Afterwards, Nicholas authorizes a meet-up with Terry to discuss the terms of reorganizing the criminal underworld under his reign. Unfortunately, the meeting turns out to be a sting operation staged by Terry — whom Nicholas instantly shoots before fleeing in the ensuing shootout.
In the course of his criminal reign, Nicholas invites Lester Arnold's outlaw motorcycle club — the Angels of Death — and the Jamaican Mafia, led by Gerald's cousin Real Badman, into the Blacklist operations; as a result, he ends up getting into disagreements with both Petrović and Elizabeta as the pair are separately in the midst of a power struggle against both the AOD and Jamaican Mafia respectively. Despite this, however, Nicholas continues to expand his nefarious empire by purchasing assets in nearly bankrupt companies and turning them back into competitive businesses. Eventually, Gracie's cocaine addiction causes her to succumb to a drug overdose and she herself ends up in hospital without mob protection; her father having already disowned her for ignoring his constant demands to stop her cocaine addiction. When Nicholas visits her, he tells her that he loves her more than her father — as she had earlier feared out of paranoia — and the two proceed to share a kiss with each other. In that moment, however, Nicholas suddenly shuts off his wife's life support and, as Gracie succumbs to a fatal cardiac arrest, he then shoots her in the head before leaving the hospital — which thereupon explodes. After covering up Gracie's murder, Nicholas persuades Giovanni to organize and host a meeting between the Five Families of "The Commission" — an illegitimate organization that consists of five cosa nostra families — under the guise of implicating one of the fellow Dons for his daughter's death.
At Gracie's funeral, Nicholas arranges for Petrović to meet him at the church once the ceremony is over. In her eulogy, Nicholas leisurely describes the true circumstances behind Gracie's death before firing a shot at the ceiling — signalling his mass security to suddenly kill the priest and the other attendees. Petrović then arrives and, after observing the massacre that had merely occurred moments ago, is killed by Nicholas. It soon becomes clear that Nicholas had arranged for the killings of his major benefactors; Formage gets executed during a cult session, Elizabeta is sexually decapitated, Yusuf's wealthy Abdul Amir gets assassinated during a public speaking, both Badman and Arnold are killed during their drug meeting — thus eliminating the two gangs altogether — and the McReary brothers get murdered alongside their accomplice Gordon Sargent. After disposing of both Gracie and Petrović's bodies, Nicholas leads his Blacklist army to infiltrate the meeting of the Five Families and stage an onslaught on all the Dons — all of whom are each executed one-by-one; before killing Giovanni himself, Nicholas confesses to Gracie's murder and announces his takeover of the criminal underworld.
With all his enemies vanquished and the rest of the criminal organizations subjugated to his influence, Nicholas has officially cemented himself as the undisputed crime kingpin of Prime. In the epilogue, one year later, Nicholas — now known under his own nickname, "The Criminal Mastermind" — mobilizes the Blacklist's next strategy in hunting down his former friend Nicky Christ and his son Junior, both of whom are affiliated with the Blacklist's new central rivals: The Streets. After contemplating his plot on killing the two, Nicholas proceeds to confront Nicky and Junior off-screen — thus setting the staging events onto Liberty.
- Nicholas Hough — An ambitious criminal mastermind and the impending founder of the Blacklist syndicate who inevitably becomes the undisputed crime kingpin of the Prime underworld.
- Terry Harvester — A professional liaison and Nicholas' money launderer.
- Gracie Ancelotti — A striptease prostitute and Giovanni's daughter who gradually becomes Nicholas' trophy-wife.
- Yusuf Amir — An influential real estate developer and the major benefactor of Nicholas' crime syndicate.
- Giovanni Ancelotti — An Italian mob boss and Don of the Ancelotti crime family; he is also Gracie's father and later becomes Nicholas' father-in-law.
- Kenny Petrovic — An illegitimate Russian crime lord and Pakhan of the Liberty City Bravta.
- Elizabeta Torres — An infamous ex-convict known as "the prison landlady" who becomes the drug kingpin of Liberty City.
- Gerry McReary — A habitual offender and the eldest brother of the McReary family.
- Packie McReary — A career criminal and the youngest brother of the McReary family.
- Lamar Davis — An enthusiastic gangbanger and The Families' chief benefactor.
- Gerald — A paranoid drug-dealer and The Families' leading figure.
- Simeon Yetarian — A crooked car-dealer and one of the employers of Nicholas Hough.
- Martin Madrazo – An international drug lord posing as a legitimate businessman and the founder of the Madrazo Cartel.
- Trevor Phillips – A psychopathic arms-dealer and the titular CEO of Trevor Phillips Enterprises.
- Tommy Vercetti — A sociopathic crime boss and the legendary crime kingpin of Vice City.
- Wade Johnson — A mysterious federal contact who is seemingly affiliated with Terry Harvester.
- Real Badman — A high-ranking member of the Jamaican Mafia who was relatively associated with Gerald.
- Lester Arnold — A ferocious gang lord and the leader of the Angels of Death outlaw motorcycle club.
- Anthony "Gay Tony" Prince — A legitimate nightclub owner and Gracie's business partner.
- Lester Crest — An individualistic cracker and Nicholas' criminal fence.
- Cris Formage — A scandalous cult baron and the leader of the Epsilon Program.
- Don Percival — A global entrepreneur and the founder 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.