This Grand Theft Auto-inspired game of violence and vengeance begins deep in Maya jungle, where a man named Ernesto Cruz was lost in 1989. The official explanation for his disappearance was fatal overdose, but this is not enough for Ernesto's twin sons, Ram and Tommy. They embark on a quest for truth, though the Mexican wilderness and underworld urban environments inhabited by gangs, drug lords, and dangerous women.

Players can explore the large areas on foot, or commandeer any vehicle they choose. Total Overdose features a fighting game-styled combo system, and smart, skilled shooting unlocks new equipment and abilities. A "Rewind" system allows players to repeat a sequence to nail a perfect combo, or even to turn back the clock and avoid a fatal mistake.