Five years after saving New York City from destruction by the shape-shifting god Gozer, the Ghostbusters have been sued for the property damage incurred and barred from investigating the supernatural, forcing them out of business. Raymond “Ray” Stantz owns an occult bookstore and works a side job alongside Winston Zeddemore as unpopular children’s entertainers. Egon Spengler works in a laboratory experimenting with human emotions, and Peter Venkman hosts a television show about psychics.

Dana Barrett, Peter’s ex-girlfriend, has an infant son named Oscar with her ex-husband and works at an art museum cleaning paintings. She turns to the Ghostbusters for help after Oscar’s baby stroller rolls, seemingly by itself, into a busy road intersection. At the museum, a painting of Vigo the Carpathian, a brutal sixteenth-century tyrant and powerful magician, comes to life and enslaves Dana’s boss Janosz Poha. Vigo orders Janosz to bring him a child to possess, allowing him to escape the confines of his painting and live again to conquer the world. Because of his infatuation with Dana, Janosz chooses Oscar.

Meanwhile, the Ghostbusters excavate the intersection where Oscar’s stroller stopped and discover a river of slime running through the abandoned Beach Pneumatic Transit system. Ray obtains a sample but is attacked by the slime and accidentally breaks a pipe which falls onto a power line, causing a citywide blackout. The Ghostbusters are arrested and taken to court for the damage and for investigating the supernatural. In the courtroom, the slime sample is presented as evidence. It responds physically to the judge’s angry tirade against the Ghostbusters and then explodes, summoning the ghosts of two brothers he sentenced to death. The Ghostbusters capture the ghosts in exchange for a dismissal of the charges and the right to resume the Ghostbusters business.

One night, the slime invades Dana’s apartment, attacking her and Oscar. She seeks refuge with Peter and they rekindle their relationship. The Ghostbusters discover the slime reacts to emotions and suspect it has amassed from the negative attitudes of New Yorkers. Determining Vigo and the slime are connected, Egon, Ray, and Winston investigate the river of slime, but they are pulled in. They emerge at the museum and begin fighting each other until Egon realizes they are being influenced by the slime.

The Ghostbusters tell the mayor of their suspicions but are dismissed; his assistant Jack Hardemeyer has them committed to a psychiatric hospital to protect the mayor’s political interests. A spirit in the form of Janosz kidnaps Oscar, and Dana pursues them into the museum, which is then covered with impenetrable slime. On New Year’s Eve, the slime rises to the streets, causing widespread supernatural chaos. Learning of Hardemeyer’s actions, the mayor fires him and has the Ghostbusters released.

Determining the need for a positive symbol to rally the citizens and weaken the slime, the Ghostbusters use positively charged slime to animate the Statue of Liberty and pilot it through the streets filled with cheering citizens. At the museum, the slime barrier partially recedes in response to the positive emotions and the Ghostbusters use the Statue’s torch to break through the ceiling, stopping Vigo from possessing Oscar. The Ghostbusters rappel through the ceiling and neutralize Janosz with positive slime. Vigo takes on physical form, immobilizes Dana and the Ghostbusters, and recaptures Oscar. The gathered crowds outside begin singing a chorus of “Auld Lang Syne”, and their positivity weakens Vigo. He is forced to return to the painting and the Ghostbusters are freed. Vigo possesses Ray, but the Ghostbusters use their weapons to free him and defeat Vigo, his painting being replaced by their likenesses surrounding Oscar. In the aftermath, the Ghostbusters are cheered by the city and the Statue of Liberty is returned to Liberty Island.
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