Los Santos is a fictional city located in San Andreas, and it is the first city encountered in Grand Theft Auto: San Andreas. Los Santos is the biggest city of the State of San Andreas. Los Santos is based on Los Angeles, California. Los Santos translates to 'The Saints', a play on Los Angeles, meaning 'The Angels'. This also applies to the two cities' nicknames - "The City of Saints" and "City of Angels".

Like Los Angeles, Los Santos is a huge, sprawling co-mingling of cultures and perspectives, full of two-bit hoodlums and small-time and really big time actors and musicians. The population of almost 1 million people is divided into 32 districts, which are home to movie and television studios, multi-million dollar estates, crack-ridden ghettos, and the fourth busiest airport in the world. Numerous roads and a central rail line connect Los Santos to San Fierro and Las Venturas. The most infamous street in the city is Grove Street, located in Ganton, southeast of downtown Los Santos, and just minutes south of East Los Santos, which contains a predominantly Hispanic population. Grove Street is home to the Families gang, a once powerful gang whose influence faded due to highly successful drug trafficking by the rival Ballas gang.

Los Santos' police are often corrupt and the politicians avoid the streets like the plague. There is a motocross track, several basketball courts, and an observatory (modeled after the Griffith Observatory) to satisfy stargazers. Occasionally, independent drug dealers are seen carrying huge wads of cash from recent transactions. Graffiti is commonplace and gambling venues like the racetrack are frequented by many of the city's denizens. The suburbs nestled in the north hills (modeled after the Hollywood Hills) are home to wealthy businessmen, movie stars, and Madd Dogg, the killer rap artist, alike. The occasional shack or trailer park can also be spotted within this highly affluent district, testaments to the period prior to the gentrification of northern Los Santos.