Following the events of Ghostbusters: Afterlife, Ghostbuster founders Raymond "Ray" Stantz and Winston Zeddemore re-establish the Ghostbusters, with the latter acquiring and reopening the organisation's old headquarters in a New York firehouse. Believing a new generation is needed to tackle the paranormal and occult, the pair recruit two new members to serve as staff members at the headquarters – Catt, the new co-ordinator and assistant; and Eddy, a technological genius assigned to labwork and research. The group soon begin recruiting a new selection of rookies to serve as Ghostbusters, shortly before Ray takes delivery of an occult relic known as the Spirit Guide, written by John Horace Tobin – a researcher of the occult, whom Ray is fascinated with.

After conducting a few jobs, the new Ghostbusters are tasked with checking in on a package from Ray and Winston's close friend Peter Venkman, which turns out to be an old ghost trap that no one at the firehouse can account for. Tasked with using it on the ghost containment unit, the trap suddenly malfunctions before a mysterious force known as "The Nameless" escapes and possesses Winston. Concerned for his friend, Ray and the others ordered the Nameless to exit his body, only to find something has tethered it to Winston. Eddy soon works to find a way to separate the pair, but his efforts backfire and cause the Nameless to open a rift into the realm of ghosts. With further research into the matter, Eddy advises the Ghostbusters to enter the rift and determine if they can find something beyond it that can free Winston.

Inside the rift, the Ghostbusters come across the spirit form of Tobin as his book - which had awakened and been creating rifts for ghosts to use - who is shocked to discover their presence. Although wishing them to leave, he allows the Ghostbusters to learn that the leather binding of the Spirit Guide, which they removed, is key to freeing Winston. Returning to the living world, Eddy uses this knowledge to create the necessary means to liberate Winston and entrap the Nameless. Satisfied with how the rookie Ghostbusters performed, Ray and Winston officially recognize them as a fully fledged Ghostbuster, with Catt supplying them a new outfit. Before Winston and Ray can treat them to a celebration meal, Catt receives call of a new job, which the Ghostbusters promptly attend to.