The game takes place in 1992, during the heyday of crime in the California metropolitan areas. The player controls the main character Carl Johnson (eng. Carl Johnson) nicknamed CJ (eng. CJ), an African American aged about 25 years. CJ returned to Los Santos after living in Liberty City for five years. He left Los Santos in 1987 due to the death of his younger brother Brian, blamed on his older brother Sean "Sweet" Johnson. He was in town for the funeral of his mother, Beverly Johnson. She was killed by Sweet's enemies during a drive-by.

On the way home, CJ is detained by Los Santos police officer Frank Tenpenny, head of the special operations unit CRASH (an acronym for Community Resources Against Street Hoodlums, literally Russian. organized crime). Tenpenny accuses CJ of killing another CRASH member, Officer Ralph Pendelbury, whom he himself eliminated after Pendelbury began investigating Tenpenny's illegal activities. Subsequently, Tenpenny and his colleague Eddie Pulaski, blackmailing Carl with trumped-up charges against him, force him to work for them, killing people who pose a threat to Tenpenny's criminal activities.