Three years after the events in Summerville, Oklahoma, Callie Spengler, her boyfriend Gary Grooberson, her children Trevor and Phoebe, and their close friends Lucky Domingo and Podcast relocate to New York City to help Winston Zeddemore and Ray Stantz re-establish the Ghostbusters. After the group captures a ghost in Hell’s Kitchen, Walter Peck, the Ghostbusters’ long-time adversary and now the city’s Mayor, threatens to shut them down.
To appease Peck, Callie removes the underage Phoebe from the team. Upset, Phoebe attempts to control her emotions by playing chess in a nearby park, where she encounters and befriends Melody, a teenage ghost who died in a fire. Meanwhile, Ray and Podcast are collecting cursed objects for examination. Nadeem Razmaadi sells them a strange brass orb with ritual markings written in Mesopotamian Arabic, inherited from his grandmother. Ray determines it is an apotropaic trap due to copper alloys typically being used in rituals against the supernatural since the Bronze Age.
When Ray evaluates its PKE levels, the orb immediately emits broad-spectrum psionic energy. A cold wave travels from the orb to the Ghostbusters’ firehouse headquarters, damaging the ecto-containment unit, which is almost at capacity. Winston takes the orb to his privately owned paranormal research center, run by Dr. Lars Pinfield. Using an experimental extraction device, he is unable to extract any spiritual energy from it. The orb’s captive psychically sabotages one of the center’s ecto-confinements, allowing a ghost to escape and hide in Podcast’s equipment.
To learn more, Lars joins Trevor and Lucky to see Nadeem, who reveals that the orb was kept hidden by his grandmother within a brass-lined chamber. Peter Venkman, brought in to help, discovers Nadeem has latent pyrokinetic powers. Meanwhile, Ray, accompanied by Phoebe and Podcast, visits Dr. Hubert Wartzki, a New York Public Library research librarian. Wartzki explains the orb was built over 4,000 years ago in Southwest Asia by four sorcerers called the Firemasters to imprison Garraka, a phantom god who sought to conquer the world with an undead army using “Kusharit Umoti” – “the power to kill by fear itself.”
Nadeem’s grandmother was of the lineage of the Firemasters, one of whom prevented Garraka from escaping the orb in 1904 during a mock ritual conducted by members of the Manhattan Adventurers’ Society, whom he froze to death. Garraka was confined in the orb due to his vulnerability to brass. This, combined with fire and the removal of his horns, trapped him within the orb. When the trio attempts to stop the escaped ghost from stealing a phonographic recording of the club’s ritual, Peck exploits Phoebe’s involvement to shut down the Ghostbusters. After an argument with Gary and her mother, Phoebe runs away and takes Melody to Winston’s research center. She uses his extraction equipment to project herself as a ghost for two minutes so the pair can physically interact.
Melody reveals she had been secretly working with Garraka, who has offered her passage to the afterlife. By controlling Phoebe’s disembodied spirit, Garraka forces her physical body to recite the ritual chant. He then escapes, locates his horns, and begins freezing the city. Realizing Garraka will free the ghosts in the containment unit after freeing ones from the center, the Ghostbusters gather to defend their headquarters. They are aided by Nadeem, who dons the Firemaster brass armor kept by his grandmother and attempts to master his powers.
Garraka overpowers them and breaches the containment unit. Phoebe electroplates Egon Spengler’s proton pack with brass to strengthen it. Melody, betrayed by Garraka, atones by helping Nadeem utilize his powers to weaken Garraka. Ray, with help from his fellow veteran Ghostbusters, including their longtime receptionist Janine Melnitz, captures Garraka by turning the ruptured containment unit into a giant ghost trap. Melody reconciles with Phoebe before departing for the afterlife to reunite with her family. As the city thaws, the Ghostbusters are hailed as heroes again, with Peck forced to support the team and reinstate Phoebe. The Ghostbusters begin pursuing escaped ghosts across New York City.
In a mid-credits scene, a trucker gets out of his Stay-Puft Marshmallows branded truck to make a purchase from a vending machine, while the Mini-Pufts steal his vehicle in his absence.