In 1992, Carl Johnson, shortly known as CJ, returns to Los Santos after spending five years living in Liberty City when his brother Sean Johnson, known as Sweet, calls to tell him that their mother has been murdered. Shortly after leaving the airport, Carl is intercepted by a group of corrupt LSPD C.R.A.S.H. officers led by Frank Tenpenny, and consisting of two other officers, Officer Edward “Eddie” Pulaski and Officer Jimmy Hernandez, with whom Carl has a history with. Tenpenny implicates Carl in the murder of a police officer, Officer Pendlebury, that Tenpenny himself committed, as he was on the verge of exposing him, and threatens to frame him for it if he does not cooperate with them.
Carl goes back to his former home on Grove Street and reunites with Sweet as well as fellow members of his old gang, Ryder and Big Smoke. Finding that the Grove Street Families (GSF) have lost much of their territory while he was gone, Carl decides to stay in town. He works with the others to re-establish the GSF, Carl gradually restores the gang to power, driving off the rival Ballas and Vagos gangs and reducing the amount of drugs on the street, and gaining the admiration of Sweet, who was disappointed that he had left Grove Street after the death of his brother Brian Johnson. While on the way to join Sweet for a final stand against the Ballas, Carl is contacted by his sister Kendl’s boyfriend, Cesar Vialpando.
Cesar brings Carl to a garage where they find Smoke and Ryder meeting with Tenpenny and a group of Ballas, learning that they had been working with Tenpenny all along, and were responsible for his mother’s murder, explaining their suspicious behaviour. Suspecting a set-up, Carl rushes to Sweet’s rescue, and fights off the Ballas, but the police arrive shortly afterwards. Sweet is thrown in jail while Tenpenny takes Carl into the countryside and dumps him there.
With the GSF in pieces, Smoke and Ryder, now openly allied with the Ballas, take over Los Santos and flood the streets with drugs. Left in the countryside, Carl works with Cesar’s cousin Catalina to make money by carrying out several heists in the area. He also meets a strange hippie called The Truth and a blind triad leader named Woozie. After winning the deed to a garage in San Fierro in a race against Catalina and her new boyfriend, Claude (from GTAIII), Carl goes there with The Truth, Cesar and Kendl to get it up and running so they can make a living. While in San Fierro, Carl crosses paths with the Loco Syndicate, Smoke and Ryder’s drug connection. Carl interupts the organization and identifies its leader, Mike Toreno. Along with Cesar and the Triad, Carl kills Ryder and the other Loco Syndicate leaders, Jizzy-B and T-Bone Mendez, and shoots down Toreno’s helicopter. Despite Toreno’s supposed death, Carl is soon contacted by him in the desert.
Toreno reveals that he is actually a government agent and enlists Carl’s help in several shady operations in exchange for Sweet’s freedom. Meanwhile, Carl travels to Las Venturas, where Woozie invites him to become a partner in the Four Dragons Casino, where the organization is facing problems from the mob families that control the city. Looking to wrest control of Venturas from them, Carl helps Woozie plot a robbery of the mob’s casino and gains the mob’s trust through various jobs for mob boss Salvatore Leone. Eventually the heist is carried out successfully, earning the Triad a place of power in Las Venturas, although causing the mob to distrust Carl.
Carl also encounters disgraced rapper Madd Dogg, whom he rescues from a suicide attempt. Grateful, Madd Dogg asks Carl to be his manager. Tenpenny, thinking his arrest is inevitable, tasks his partner Eddie Pulaski with killing Carl and disposing of the body of another C.R.A.S.H. officer Jimmy Hernandez, who was informing on them. Pulaski manages to attack, leading him being consequently killed, but Carl pursues and kills him. Madd Dogg comes back from rehab, prompting Carl to return to Los Santos to get his music career started again. Toreno contacts Carl for one last favor, destroying some spy ships in the area, and finally has Sweet released from prison. Now being rich and successful, Carl attempts to cut Sweet in on his businesses, but Sweet becomes angry that he ran away and let their home be taken over by drug dealers to make his fortune.
While Carl helps Sweet once again drive off the rival gangs, Tenpenny is tried for several felonies but the charges are surprisingly dropped due to lack of evidence, prompting a city-wide riot. Sweet soon learns that Smoke is holed up in a fortified crack den in the city, and seeking to stop the flow of drugs on the street, he and Carl go there to confront him. Carl enters the building alone, fighting his way to the top floor and battling Smoke.
As Smoke is killed, Tenpenny appears and steals Smoke’s drug money, intending to use it to leave the city before the rioters kill him. He rushes out of the building and Carl and Sweet pursue him as he flees in a fire truck. Soon, Tenpenny loses control of the truck, driving off a bridge and crashing at the entrance to Grove Street. Carl and his friends watch as Tenpenny crawls from the wreckage and dies of his injuries.
In the aftermath Carl’s family and friends arrive at the Johnson house for a meeting. Cesar proposes to Kendl and Madd Dogg announces his first gold record. As his friends and allies celebrate their success, Carl turns to leave. When Kendl asks where he’s going, he replies, “Fittin’ to hit the block, see what’s happening”.