Nine years after a robbery in Ludendorff, North Yankton, went wrong, former bank robber Michael Townley is living under witness protection with his family in Los Santos, San Andreas, under the name of Michael ‘De Santa’. Franklin Clinton, who works as a repo man for a car dealership alongside his best friend Lamar Davis, is asked to repossess a car from Michael’s 20 year old son Jimmy, who is overdue on his loan payment. Correctly deducing that his son is about to become a victim of credit fraud, Michael confronts Franklin and orders him to crash the car through the dealership’s window. Franklin is fired, but he and Michael become friends. When Michael discovers his wife Amanda in bed with her tennis coach, he and Franklin chase the man to a mansion, which Michael destroys out of anger. The mansion’s owner, the Mexican drug lord Martin Madrazo, demands compensation, so Michael and Franklin perform a jewellery shop heist to pay their debt. Michael’s sole surviving partner in the Ludendorff robbery, Trevor Philips, hears of the jewellery heist and realises that Michael’s death was faked and that the heist was his handiwork. The two reunite after Trevor tracks Michael down in Los Santos.
The personal lives of the protagonists begin to spiral out of control. Trevor’s unexpected reappearance triggers reckless and erratic behaviour in Michael, which prompts his family to leave. Michael’s attempts to make something of himself bring him into conflict with Devin Weston, a self-made billionaire venture capitalist and corporate raider who develops a grudge against him and vows revenge. Franklin becomes disturbed by the way Lamar falls under the influence of gangster Harold “Stretch” Joseph, who defected to a rival gang in prison and repeatedly attempts to kill Lamar to prove himself to his new brethren. Trevor’s reckless efforts to consolidate his control over the methamphetamine market in Blaine County see him waging war against the San Andreas chapter of The Lost outlaw motorcycle club, a number of Latin American street gangs, rival meth dealers, government-sponsored mercenaries and Triad kingpin Wei Cheng.
FIB government agents Dave Norton and Steve Haines contact Michael and demand that he perform a series of operations with Franklin and Trevor to undermine a rival agency, the IAA. Under Haines’s direction, they attack an armoured convoy carrying funds intended for the IAA and raid a bank containing the payroll for all of the corrupt police and public officials in Los Santos. Michael and Trevor perform a job for the drug lord Madrazo, and Trevor demands compensation for their efforts. He kidnaps Madrazo’s wife instead, temporarily forcing himself and Michael into hiding. As Haines comes under increasing scrutiny for his methods, he forces them to infiltrate the FIB headquarters and erase any evidence being used against him from their servers. Michael takes the opportunity to wipe any data on his own activities in the process, destroying Haines’s leverage on him. After Trevor returns Madrazo’s wife, the trio start making plans for their most daring feat ever: raiding the Union Depository’s gold bullion reserve.
After returning to Los Santos, Michael makes amends with his family and they start living together again. Trevor, however, discovers that a former Ludendorff heist accomplice was not in prison as he was led to believe, but killed during the heist and buried in the grave marked for Michael. Trevor’s feelings of betrayal cause friction within the group and threaten to undermine their Union Depository plans. When Michael and Norton are caught in a Mexican stand-off between the FIB, IAA and private security firm Merryweather, Trevor aids in their escape, holding that only he has the right to kill Michael. Despite not forgiving Michael, Trevor still wants to perform the Union Depository heist; the duo agree to part ways afterwards.
The Union Depository heist is completed successfully, however Franklin is approached by two parties separately who demand that he kill Trevor or Michael. Haines and Norton contend that Trevor is a liability, and Weston wants retribution for Michael’s betrayal. Franklin has three choices: kill Michael, kill Trevor or kill neither and face their enemies together. Should Franklin kill either Michael or Trevor, he ceases contact with the survivor and returns to his old life. Should he kill neither, the trio join forces to withstand an onslaught from the FIB and Merryweather before going on to kill Weston, Stretch, Cheng and Haines. With all their enemies disposed, the three stop working together, but remain friends.