Plot

A young street hustler, a retired bank robber and a criminal entrepreneur rob banks and do heists, and do dangerous missions in Los Santos, Blaine County and Paleto Bay. These criminals are very different and have very different backstories. The game takes place in Southern San Andreas.—Rockstar Games

In 2004, criminals Michael Townley, Trevor Philips, and Brad Snider partake in a failed robbery in Ludendorff, North Yankton, resulting in Michael being presumed dead. Nine years later, Michael lives with his family in the city of Los Santos under the alias Michael De Santa, having made a secret agreement with a Federal Investigation Bureau (FIB) agent, Dave Norton, to stay hidden. Across town, gangbanger Franklin Clinton works for a corrupt car salesman and meets Michael while attempting to fraudulently repossess his son's car. The two later become friends. When Michael finds his wife sleeping with her tennis coach, he and Franklin chase the coach to a mansion, which Michael wrecks in anger. The owner of the mansion, drug lord Martin Madrazo, demands compensation for the damage, so Michael returns to a life of crime to obtain the money, enlisting Franklin as an accomplice. With the help of Michael's old friend Lester Crest, a disabled hacker, they rob a jewellery store to pay off the debt. Meanwhile, Trevor, who lives in squalor in rural Blaine County, hears of the heist and recognises Michael's work; Trevor had believed the FIB killed Michael in the Ludendorff heist. Trevor finds Michael and reunites with him, forcing the latter to reluctantly accept the former back into his life.

As time goes on, the protagonists' lives spiral out of control. Michael's criminal behaviour prompts his family to leave him. When he later becomes a movie producer, he comes into conflict with Devin Weston, a billionaire venture capitalist and corporate raider, who attempts to shut down Michael's studio. Michael thwarts his efforts and inadvertently kills his lawyer, to which Devin vows revenge. Meanwhile, Franklin has to rescue his friend Lamar Davis from rival gangbanger Harold "Stretch" Joseph, who attempts to kill him multiple times. Concurrently, Trevor tries to consolidate his control over various black markets in Blaine County, waging war against The Lost outlaw motorcycle club, Latino street gangs, rival meth dealers, the private military company Merryweather, and triad kingpin Wei Cheng.

Having broken his agreement with Dave by committing robberies again, Michael is coerced by Dave and his superior, Steve Haines, to perform a series of operations alongside Franklin and Trevor to undermine the International Affairs Agency (IAA).[k] Under Steve's direction and with Lester's help, they attack an armored car carrying funds for the IAA and steal an experimental nerve agent from an IAA lab. As Steve comes under increasing scrutiny, he forces Michael and Franklin to break into the FIB building and erase evidence against him from the servers. Michael takes the opportunity to wipe the data on his activities, destroying Steve's leverage over him.

After reconciling with his family, Michael starts planning his final heist with Trevor, Franklin, and Lester: raiding the Union Depository's gold bullion reserve. However, Trevor discovers that Brad was not imprisoned as he was led to believe, but killed during the Ludendorff heist and buried in the grave marked for Michael. Deducing the heist was a setup and that he was supposed to be killed in Brad's place, Trevor feels betrayed and leaves Michael for dead during a shootout with Cheng's henchmen. Although Franklin rescues Michael, Trevor's anger towards the latter causes friction within the group and threatens to undermine their plans. Meanwhile, Steve attempts to arrest Michael, but they, alongside Dave, become caught in a Mexican standoff between the FIB, the IAA, and Merryweather. Steve escapes while Michael and Dave are saved by Trevor, who believes only he has the right to kill Michael.

The Union Depository heist is successful, but Franklin is afterwards approached by Steve and Dave, who contend that Trevor is a liability, and Devin, still seeking vengeance on Michael. Franklin has three options: kill Trevor, kill Michael, or attempt to save both in a suicide mission. Should Franklin choose to kill either Michael or Trevor, his relationship with the other ceases, and he returns to his old life. Otherwise, the trio, aided by Lamar and Lester, withstand an onslaught from the FIB and Merryweather before going on to kill Cheng, Stretch, Steve, and Devin. Michael and Trevor reconcile, and the three protagonists cease working together but remain friends.