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 world environment in which to move around. On foot, the player's character is capable of walking, eating, running, sprinting, swimming, climbing (the first GTA game in which swimming and climbing are possible) and jumping as well as using weapons and various forms of hand to hand combat. Players can drive a variety of vehicles, including automobiles, buses, semis, boats, fixed wing aircraft, 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 and look around the cities, eat from the restaurant, or cause havoc by attacking people and causing destruction. 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 pedestrians, pointing guns at people, stealing vehicles, manslaughter, etc.), whereas SWAT teams, the FBI, and the military respond to higher wanted levels.