San Andreas is structured similarly to the previous two games in the series. The core gameplay consists of elements of a third-person shooter and a driving game, affording the player a large, open environment in which to move around. On foot, the player's character is capable of walking, running, swimming (the first GTA game in which swimming is possible), climbing and jumping, as well as using weapons and various forms of hand to hand combat. Players can steal and drive a variety of vehicles, including automobiles, boats, airplanes, helicopters, trains, tanks, motorcycles and bikes. Players may also import vehicles rather than steal them.
The open, non-linear environment allows players to explore and choose how they wish to play the game. Although storyline missions are necessary to progress through the game and unlock certain cities and content, they are not required, as players can complete them at their own leisure. When not taking on a storyline mission, players can free-roam. However, creating havoc can attract unwanted and potentially fatal attention from the authorities. The more chaos caused, the stronger the response: police will handle "minor" infractions (attacking people, pointing guns at people, stealing cars, killing a few people, etc.), whereas SWAT teams, the FBI, and the military respond to higher wanted levels.
The player can also partake in a variety of optional side missions. The traditional side missions of the past games are included, such as dropping off taxi cab passengers, putting out fires, driving injured people to the hospital and fighting crime as a vigilante. New additions include robbery missions, pimping missions, truck and train driving missions requiring players to make deliveries on time, and driving/flying/boating/biking schools, which help players learn skills and techniques to use in their corresponding vehicles.
Unlike Vice City and GTA III, which needed loading screens when traveling between different districts of the city, San Andreas has no load times when the player is in transit (which is notable, given how much larger the in-game map is than in the previous games). The only loading screens in the game are for cut-scenes and interiors. Other differences between San Andreas and its predecessors include the switch from single-player to multiplayer Rampage missions (albeit not in the PC version), and the replacement of the 'hidden packages' with spray paint tags, hidden camera shots, horseshoes, and oysters to discover.
The camera, fighting, and targeting controls were reworked to incorporate concepts from another Rockstar game, Manhunt, including various stealth elements, as well as improved target crosshairs and a target health indicator which changes colors from green to red to black depending on the target's health.
In addition, players can swim and climb walls for the first time in the series. The ability to swim has a great effect on the player as well, since water is no longer a viable barrier to the player and can no longer instantly kill the player (although it is possible to drown). For greater firepower, players can also wield dual firearms or perform a drive-by shooting with multiple gang members. Also, due to the immense size of San Andreas, a waypoint reticule on the HUD map can be set, aiding the player in reaching a destination.
The game's artificial intelligence was also improved. No longer can the player beat a pedestrian to death on a busy street in broad daylight and have bystanders not respond. While most pedestrians will flee or duck for cover, some armed civilians such as drug dealers and enemy gang members will attack CJ, and friendly gang members will shoot at and pursue his opponents. Cops will now chase other rival gang members who are committing crimes, instead of just the player.
The characters that appear in San Andreas are relatively diverse and relative to the respective cities and locales which each of them based himself in. This allows the game to include a significantly wider array of storylines and settings than in Grand Theft Auto III and Vice City. The player controls Carl "CJ" Johnson, a young African-American gang member.
The Los Santos stages of the game revolve around the theme of the Grove Street Families gang fighting with the Ballas and the Vagos for territory and respect. East Asian gangs (most notably the local Triads) and an additional Vietnamese gang are evident in the San Fierro leg of the game, while three Mafia families and the Triads who all own their respective casino are more prominently featured in the Las Venturas section of the game.
Like the previous two GTA games, the voice actors of San Andreas include notable celebrities, such as David Cross, Andy Dick, Samuel L. Jackson, James Woods, Peter Fonda, Charlie Murphy, Frank Vincent, Chris Penn, Danny Dyer, Sara Tanaka, rappers Ice T, Chuck D, Frost, MC Eiht and The Game and musicians George Clinton, Axl Rose and Shaun Ryder.
Young Maylay makes his debut as the protagonist, Carl.
After living in Liberty City for five years, Carl "CJ" Johnson returns home to Los Santos for his mother's funeral. There, he finds his family and gang, the Grove Street Families, in disarray. While ironing out issues with his fellow gang members and fighting enemy gangs for territory within the city, Carl begins to bring the Grove Street Families back to prominence. However, with the Families on the cusp of retaking control of Los Santos, he discovers that his best friends, Big Smoke and Ryder, are working with the crooked Officer Frank Tenpenny and Grove Street's rival gang, the Ballas. Smoke and Ryder set a trap and help the Ballas ambush Sweet, Carl's brother. Tenpenny sends the police to arrest Sweet and kidnap Carl, whom Tenpenny ditches in the distant rural countryside. Carl, realizing Tenpenny is his only hope of staying out of jail or getting Sweet released, continues to run the cop's crooked errands, in the process killing or discrediting people involved in building a criminal case against Tenpenny.
Carl steadily befriends new allies, among them blind Chinese Triad leader and businessman Wu Zi Mu, an old hippie called The Truth, and Cesar Vialpando, a Hispanic gang member who, like Carl, has been betrayed by his old friends. Carl and his friends open a garage in San Fierro while they wait for an opportunity to return to Los Santos. After finding and killing Ryder, Carl becomes immersed in the affairs of a shady government agent, Mike Toreno, who implies that he will release Sweet if Carl helps him with his covert operations. Then, Carl works alongside Wu Zi Mu to promote the growth of a new casino in the mafia-run Las Venturas. Carl also aids a failed famous rapper Madd Dog back on the spotlight by becoming his manager (since he caused his career's downfall). Consequently, Carl enjoys newfound wealth and eventually returns to Los Santos. Toreno makes good on his earlier promise to release Sweet, but much to Carl's surprise, his brother wants no part of Carl's new lifestyle. Sweet insists on returning to the hood and working to reestablish the GSF rather than rest on the laurels of Carl's success.
Tenpenny goes to trial for several felonies, but the charges are dropped for lack of evidence, as all the prosecution's witnesses are either missing or dead. Tenpenny's release sends the citizens of Los Santos into a citywide riot, similar to the 1992 Los Angeles Riots. Fueled by Sweet's resolve to topple Big Smoke, who has become the city's biggest drug kingpin, Carl reacquires lost gang territory and hunts down the traitors responsible for pushing drugs that destroyed the Families. He kills Big Smoke in a shootout, escapes from the burning crack palace and Tenpenny shows up and flees with Smoke's drug fortune. Sweet and Carl pursue Tenpenny through the streets of Los Santos in a car chase. Tenpenny loses control of his firetruck, and he drives it off a bridge. Carl is about to shoot him, "just to make sure it's finally over," but is stopped by Sweet. Sweet simply tells him, "It's just a cop that died in a car accident." Tenpenny then dies from his injuries. The final scene shows the Johnson family reunited. As his friends and allies celebrate their success, Carl turns to leave. When asked where he's going, he replies, "Fittin' to hit the block, see what's happening."