Trevor manages to escape by taking a civilian women hostage. The next scene takes us to Michel’s funeral. However, the person actually buried happens to be Brad. It turns out that Michael is alive and is watching the funeral out from the shadows, smoking his cigarette. Michel Townley enters into witness protection program with his family in the city of Los Santos in the state of San Andreas, assuming the name Michael de Santa.
The game jumps forward to 2013. Franklin Clinton, who works with his best buddy Lamar Davis as a repo man for a car dealer receives order from his boss about repossessing the car of Jimmy, the 20-year old son of Michael, who has just bought a car but is late for the credit installment payments. When Franklin gets the car and returns the dealer, Michael appears on the rear seat of the car. Michael, who is aware that his son is about to fall victim of a loan scam, orders Franklin to crash the car to the dealership and Franklin crashes the car into the dealership as he says.
After this, Franklin is fired from his job but forms a friendship with Michael. Michael, who catches his wife Amanda on the act with her tennis trainer, pursues the trainer to his mansion with Franklin. They demolish the mansion but it turns out that the mansion is owned by the Mexican Drug Lord Martin Madrazo. Medrazo, who is furious for this incident, asks Michael to pay the costs in relation with the mansion. Michael decides to rob a jewellry store to pay off Madrazo’s demand with the spoil with his old friend Lester Crest and he carries out the robbery. Trevor Philips, the sole survivor of Ludendorff heist becomes aware of this robbery and realizes that the mastermind behind the robbery is no other than his old buddy Michael, who he thinks is dead. He then finds his trace in Los Santos and faces with his old partner.
The personal lives of the characters begin spinning out of control from that point forward. The unexpected reappearance of Trevor makes Trevor exhibit selfish and erratic behavior. This leads to his family leaving him. In time, Michael makes en enemy of Devin Weston, a rich billionaire entrepreneur and magnate. As the result of the unfolding events, Weston starts nursing a grudge against Michael and vows revenge.
Franklin is not happy with the actions of Harold “Stretch” Joseph, a sellout gangster who switched to the rival gang in the prison and who attempted to kill Lamar numerous times in order prove himself up to his new gang buddies.
The Trevor on the other hand, during his struggle to cement its methamphetamine market that he controls in Blaine County, enters into a war against the San Andreas Chapter of Lost Bike Bang, against various Latin American street gangs, rival methamphetamine dealers, state backed mercenaries, and against the Chinese Triad, led by Wei Chang, one of the most influential figures of the underground world.
Michael, in order to torpedo the IAA, the rival of the FBI, is forced by two FBI agents, Dave Norton and Steve Hines to undertake a series of operations with Franklin and Trevor. Under the instructions of Heines, they attack on a armored vehicle convoy that is carrying a monetary source, belonging to IAA and they rob a bank that holds the payrolls of all corrupted cops and state employees in Los Santos. When Haines faces the point, where a possible investigation on him is about to be initiated, he forces Michael and his crew to infiltrate the Central FBI Offices and to erase all kinds of incriminating evidences about him from the files. Michael, who sees this as an opportunity to end the pressure he is putting on him, removes all the evidences of his past activities while erasing his file.
Michael and Trevor undertake a job for Madrazo and Trevor wants to get compensated for his work for Madrazo. But instead, he ends up kidnapping his wife. This puts both his and Trevor’s life in danger and causes them both to go underground and hide for a while. After Trevor delivers Madrazo’s wife back, the trio begin plotting the largest heist ever. Robbing the gold bar reserves of the Union Depository.
After returning to Los Santos, Michael straightens the things out with his family and they began living together once again. However, Trevor learns that Brad, one his partners in crime is not in jail as he thinks but rather resting in peace in Michael’s grave. He thinks he was betrayed by Michael and this leads to awkward conflicts, putting the heist plans they made for Union Depository at risk.
When Michael and Dave Norton is trapped in a Mexican Standoff between FBI, IAA and the private security contractor Merryweather, Trevor comes into the scene and saves Michael. He states that the only reason that he saves Michael despite all the things is because he doesn’t want anybody else to kill Michael except him. Although Trevor does not forgive Michael, he accepts to part ways after they successfully pull the heist off.
The trio of Franklin, Michael and Trevor successfully complete the Union Depository heist.
Sometime later, Franklin is forced to kill Trevor by Heines and is forced to kill Michael by Weston and finds himself into a dilemma. Franklin now has three options; killing Trevor, killing Michael or letting both live and to face with his own enemies. The player now decides on which options will be chosen. If Franklin kills either Michael or Trevor, he cuts ties with the remaining characters and he gets back to his former life. As an alternative if he does not kill any of them, the trio, against all odds, joins forces and head down on a mission to kill Haines, Stretch, Wei and Weston. After all the enemies are eliminated, they quit pulling off jobs together but remain as friends.