In 1992, after five years in Liberty City, gangster Carl 'CJ' Johnson Young Maylay returns to Los Santos after his mother's death in a drive-by shooting. He is intercepted by corrupt C.R.A.S.H. officers led by Tenpenny Samuel L. Jackson, who threaten to implicate CJ in the killing of a fellow police officer unless he cooperates. CJ returns to Grove Street and reunites with his brother Sean 'Sweet' Johnson Faizon Love, sister Kendl Johnson Yolanda Whitaker, and members of his old gang, Big Smoke Clifton Powell and Ryder MC Eiht. Discovering the Grove Street Families (GSF) have lost much of their territory, CJ restores the gang to power by helping reunite the various GSF sets who had splintered and allying himself with Cesar Vialpando—Kendl's boyfriend and leader of the Varrios Los Aztecas gang. CJ and Cesar witness Tenpenny and the rival Ballas betray the GSF and are responsible for killing CJ's mother. Suspecting a set-up, CJ rushes to Sweet's aid in a showdown against the Ballas.
Sweet gets wounded in the ambush and imprisoned, while Tenpenny exiles CJ to the countryside, where he forces him to eliminate witnesses to C.R.A.S.H.'s corruption in exchange for Sweet's safety in prison. CJ befriends an ageing hippie and marijuana farmer named "the Truth" (Peter Fonda) and Triad leader Wu Zi Mu (James Yaegashi). He participates in a street race and wins a garage in San Fierro, which he sets up to earn money, and crosses paths with the Loco Syndicate, Big Smoke and Ryder's drug connection. Infiltrating the organisation, he identifies its leader: the affable but mysterious Mike Toreno James Woods. Alongside Cesar and the Triad, CJ destroys the Loco Syndicate's drug factory, killing Ryder and the other leaders except Toreno, who reveals himself an undercover agent. He enlists CJ's help in several shady operations in exchange for Sweet's release from prison. Meanwhile in Las Venturas, CJ and Wu Zi Mu establish a casino and clash with the Mafia.
After his release, Sweet and CJ revive the GSF, drive off the rival gangs from their territory, and rebuild throughout Los Santos. Tenpenny is arrested and tried for several felonies, but the charges are dropped due to lack of witnesses, prompting a city-wide riot. CJ soon discovers Big Smoke's hideout. The two engage in a gunfight; CJ wins, and before dying, Smoke confesses that he got caught up in money and power. Tenpenny arrives, holds CJ at gunpoint, steals Smoke's drug money, and escapes after causing an explosion in the building. He drives off in a fire truck, followed by CJ and Sweet, but eventually loses control and crashes over the side of a bridge overlooking Grove Street. CJ and his friends watch as Tenpenny dies of his injuries, ending the riot. In the aftermath, CJ's family and friends celebrate their success at the Johnson house. In the midst of the celebrations, CJ leaves to check on the neighbourhood.
