Michael Townley, Trevor Phillips and their partners participate in a failed bank heist which ends up in the death of their friends in the city of Ludendorff, district of North Yankton. Nine years later, Michael who now lives under the alias Michael de Santa, is protected by the witness protection program in the city of Los Santos, San Andreas. He enjoys a fake perfect life with a wife who constantly cheats on him, a son and a daughter who hates him and has recurrent nightmares about his criminal past.

Decided on ending his wife’s affair once and for all, Michael chases his wife's secret lover and destroys his house in anger, only to find out that the house in question was not his and actually belongs to the girlfriend of a Mexican drug lord names Madrazo. Michael now has a debt with drug dealer Madrazo, who demands a compensation for the incident. Michael calls his contact Franklin, a car robber he met a week prior, and arranges a jewelry heist to pay for his debt and give Franklin an opportunity to help him solve his financial problems.

After successfully stealing from the jewelry shop, the news channels all over the region highlight the case, and Trevor Phillips who is now living in the country finds out that his old friend Michael is still alive. He goes looking for Michael to reunite again with his friend, but what he doesn’t know is that Michael betrayed their partners to get away alive back in the Ludendorff failed robbery attempt. Now, playing with all 3 characters, you must overcome their personal issues and work together as a team.

Complete exciting missions from bank heists to plane hijacks. Travel across the beautiful and highly detailed map of San Andreas using car, bikes, planes or boats, and discover what is going to happen with the trio’s fragile relationship while fighting drug dealers, gangs and the FBI agents.