Ghostbusters is a tie-in to the 2016 Ghostbusters movie as a reboot of a franchise. However, there are no ties to the film's story or any of the characters. It is described as set after the events of the movie and follows the adventures of a group of four nameless Ghostbusters in Manhattan. They receive tasks at various locations, sometimes with multiple levels for each one. The locations, unlocked gradually, include Aldridge Manor, St. Lou's Cemetery, Wavering Hills Asylum, 13th Street Station, The Queen Charlotte and Limbo. The game is played with up to four local players who can each control a Ghostbuster on the same screen. When playing alone the other characters are controlled by the CPU. There are two male and two female characters with different statistics for health, speed, damage and weapon overheat. They also have a unique weapon and grenade type.

The characters follow a largely linear path in the environment with twin stick controls for movement independent from the shooting direction. Each character has a main weapon such as a rifle, shotgun, mini-gun or pistols used to take out ghosts. A grenade can be thrown as a secondary attack, with some time before it is available again. Grenades include a flashbang, electro-shock, dark matter and slime. The main weapon can overheat, so sometimes it is required to wait a little or use a separate key to empty the heat meter. Points are distributed among the group members for attacks and kills. They can also assist each other in various ways, including revives when dead. At all times the P.K.E. meter can be activated to scan the environment for paranormal activity. This is required to locate special green spots for points, or to track purple trails that generally lead to a strong enemy. While P.K.E. is activated, movement is slower. Many items in the environments are destructible and can be shot for additional points.

Stronger ghosts cannot be defeated entirely with the primary weapon. When their health meter is empty it is needed to switch to the proton beam. That one cannot overheat and a circling mechanic is used to aim the beam in a certain direction, which changes constantly, shown through an icon with a red arrow. When the correct angle has been held for some time to fill a meter, the ghoul can be slammed and after a few slams it can be trapped, with a button-mash sequence for a points multiplier. Enemy attacks can be evaded through dodge rolls and often health packs can be found. Many levels have optional collectibles.

The points add to a leveling system and with each new character level skill points are provided to upgrade a character for various statistics and abilities. In a separate containment unit section of the game all the ghosts that were encountered can be viewed in detail.