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, or cause havoc by attacking people and causing destruction. 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 that can also boost their character's attributes or provide another source of income. 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 burglary 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. The PC version of the game implements mouse chording; the player has to hold the right mouse button to activate the crosshairs, and then click or hold at the left mouse button to shoot or use an item, such as a camera.

The player has a gunfight with members of an enemy gang, the Ballas.

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 an impassable barrier that kills 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.

RPG features in character development

Rockstar has emphasized the personalization of the main protagonist by adding many RPG features. Clothing, accessories, haircuts, jewelry, and tattoos are now available for purchase by CJ, and have more of an effect on non-player characters' reactions than the clothing in Vice City. CJ's level of respect among his fellow recruits and street friends varies according to his appearance and actions, as do his relationships with his girlfriends. Players must also ensure CJ eats to stay healthy and also exercises properly. The balance of food and physical activity has an effect on his appearance and physical attributes.

San Andreas also tracks acquired skills in areas such as driving, firearms handling (when skills are high enough, double-wielding of certain weapons is possible), stamina, and lung capacity, which improve through use in the game. CJ may also learn three different styles of hand-to-hand combat (boxing, kung fu and kickboxing) at the gyms in each of the game's three cities. CJ can also speak with a number of pedestrians in the game, responding either negatively or positively. According to Rockstar, there are about 4,200 lines of spoken dialogue.

Vehicles

In total, there are nearly 200 types of vehicles in the game compared to the approximately 85 in GTA III. New additions include bicycles, dune buggies, a combine harvester, a street sweeper, a hovercraft, etc. Car physics and features are similar to the Midnight Club series of street racing games, allowing for much more midair vehicle control as well as nitrous upgrades and aesthetic modification.

There are several different classes of vehicles that serve different purposes. Off-road vehicles perform better in rough environments, while racing cars perform better on tracks or on the street. Jets are fast, but usually need a runway to land. Helicopters can land almost anywhere, but are slower. While previous Grand Theft Auto games had only a few aircraft that were difficult to access and fly, San Andreas has 11 airplanes and nine helicopters and makes them more integral in the game's missions. Several boats were added, while some were highly modified.

Other additions and changes

Other new features and changes from previous Grand Theft Auto games include:
Gang wars: Battles with enemy gangs are prompted whenever the player (either alone or accompanied by fellow Grove Street Families members) ventures into enemy territory and kills at least three gang members. If the player then survives three waves of enemies, the territory will be won and fellow gang members will begin wandering the streets of these areas. The more territory owned by the player, the more money that will be generated. Occasionally, the player's territory will come under attack from enemy gangs and defeating them will be necessary to retain these areas. Once all marked territories are claimed for the Grove Street Families, they no longer come under attack.
Car modification: Most automobiles in the game can be modified and upgraded at various garages. All car mods are strictly visual apart from a nitrous oxide system which gives the car a speed boost when activated; and hydraulics, which lowers the car's height by default and allows the player to control various aspects of the car's suspension. Other common modifications include paintjobs, rims, body kits, side skirts, bumpers and stereo system upgrades.
Burglary: Continuing the series' tradition of controversy, home invasion is included as a potential money-making activity. By stealing a burglary van, CJ is able to sneak into a residence at night, and cart off valuables or shake down the occupants.
Minigames: Numerous minigames are also available for play in San Andreas, including basketball, pool, rhythm-based challenges (dancing and 'bouncing' lowriders with hydraulics), and video game machines that pay homage to classic arcade games. In addition, there are the aforementioned casino games and methods of gambling, such as betting on virtual horse races.
Money: The money system has been expanded upon, compared to previous titles. Players can spend their cash on gambling, tattoos, meals, etc. Excessive gambling loss can force the player to sink into debt, which is shown in red negative numbers. When the player leaves a safehouse, CJ gets an unexpected call and a mysterious person tells him about his debts. Four gang members suddenly appear and shoot Carl on sight if he does not erase the debt when the mysterious person calls him a second time.
Multiplayer: Rampages have been modified to allow two players to complete them. The players are both shown simultaneously on the screen, meaning they must stay within close proximity of each other. The multiplayer Rampages were removed from the PC version of the game. However, for the PC version, there are also online multiplayer mods called Multi Theft Auto: San Andreas and San Andreas Multiplayer (SA-MP) which allow players to connect with hundreds of people online through various servers and fan-made game modes.