Having just made it back onto the streets of Liberty City after a long stretch in maximum security prison, Tommy Vercetti is sent to Vice City by his old boss, Sonny Forelli. They were understandably nervous about his reappearance in Liberty City, so a trip down south seemed like a good idea. But all does not go smoothly upon his arrival in the glamorous, hedonistic metropolis of Vice City. He's set up and is left with no money and no merchandise. Sonny wants his money back, but the biker gangs, Cuban gangsters, and corrupt politicians stand in his way. Most if not all of Vice City seems to want Tommy dead. His only answer is to fight back and take over the city himself."

The plot follows two fireteams of human supersoldiers: Blue Team, led by Master Chief, and Fireteam Osiris, led by Spartan Locke. When the former goes absent without leave to track down the artificial intelligence construct Cortana, Master Chief's loyalty is called into question and Fireteam Osiris is sent to retrieve him.

The game begins on the night of Friday 24 July 1998. The Special Tactics and Rescue Service, a police special forces unit consisting of ex-soldiers and scientists, has been assigned into the Arklay Mountains to investigate a series of cannibalistic homicides conducted by an unidentified group of people. Split into two teams, the "Bravo Team", sent out the previous night, has ceased radio contact, forcing the "Alpha Team" to investigate their disappearance on top of completing the mission.