Mafia III is the third main game in the crime series with free-roaming gameplay combining fighting, shooting and racing, on foot and using vehicles. This time the protagonist is Lincoln Clay. He is a veteran of the Vietnam War and part of a black mob. The game is set in 1968 in New Bordeaux, a fictional environment inspired by New Orleans, which consists of ten districts. There are busy city environments, but also large stretches of swamps, the countryside, canals ... When circumstances force Clay to pay back a debt to the Marcano crime family, he is betrayed and his mob friends along with his surrogate father Sammy are all killed. Left for dead, he is rescued by his friend Father James and gets in touch with his former Vietnam CIA handler John Donovan. Clay is out for revenge to destroy the Marcano family and seize control of New Bordeaux. The story is told as flashbacks by survivors in different segments incorporating cut-scenes.

Next to the various missions there is a larger, faction/assets system where decisions influence the alliance with three important characters. There is Cassandra who leads the Haitian mob, Thomas Burke with ties to the IRA and the Italian gangster Vito Scalleta, the protagonist of Mafia II, who had to leave Empire Bay after killing the don Falcone. Lincoln is mostly on his own and needs their support to hold the territory he captures. Territory does not only provide an income, each faction assigned to it also provides different types of services such as muscle, providing cars and locations or arms dealers, sabotaging phone lines to prevent back-up, bribing the police etc. similar to a skill tree where new abilities are unlocked. A district is taken over after a number of rackets have been captured along with killing the capo who leads it. Each faction also provides a constant stream of missions in the open world with a cash reward.

As in the previous games there is free-roaming gameplay where any vehicle can be stolen and driven. Different types of gameplay styles are possible, involving melee fights or ranged gunplay, with brute force or using a stealth approach combined with a cover system. Using a wiretapping junction box or with the Inside Man bonus it is possible to eavesdrop and see enemies through walls using Clay's Intel Vision, similar to the Eagle Vision of Assassin's Creed. Enemies can be lured away by whistling. Missions include infiltration, killing targets, performing heists, destroying goods, stealing cars, intercepting drugs etc. Large buildings are often used for missions played inside that specific location. There is also a large amount of collectibles including different magazines, paintings and old album covers. Not all missions are scripted, some events are triggered based on actions in the environment or attacks by hit squads. When the police becomes involved, there is a blue search zone that needs to be escaped. NPCs will often report crimes and they can be killed to prevent this, but this often leads to a chain reaction.