Mafia 2 is a largely cinematic game with a plot that unfolds in cutscenes and dialogue every few minutes. The story focuses on Vito Scaletta, an Italian-born American who returns to the fictional US city 'Empire Bay', after fighting two years with the Allied Forces in World War II.

Upon returning home to his mother and sister, it's revealed that their late father is indebted to a powerful loan shark and that they must pay the debt back by the end of the week.

Realizing that honest work at the docks will not earn fast money, Vito turns to his best friend Joe Barbaro for work and is introduced to a number of high ranking members of three powerful crime families, who send Joe and Vito on a number of high risk jobs, with even simple jobs such as selling stolen cigarettes in a car-park or buying a kilo of heroine being the catalyst for a gang war.