Ectoplasm oozes out of a crack in a New York City sidewalk as Dana Barrett pushes her baby, Oscar, in his stroller in front of her apartment building. When she stops to talk to the building superintendent, the baby carriage takes off by its own volition. It shoots into the traffic, stopping inches from an oncoming bus. Across town, parapsychologist Dr. Raymond “Ray” Stantz and Winston Zeddemore arrive at an apartment in full "Ghostbusters" regalia to entertain at a child’s birthday party. One of the children tells them that according to his father, they went out of business because they were scam artists. Later, Dana visits Dr. Egon Spengler and voices her fears that something supernatural was after Oscar. Although the Ghostbusters were disbanded when a court injunction prohibited them from investigating any paranormal activities, Egon agrees to investigate if he can enlist Ray’s help. Dana agrees as long as her former lover, Dr. Peter Venkman, is not included. Meanwhile, Peter hosts a television show called “World of Psychics,” and speaks with a clairvoyant guest who predicts the world will end on New Year's Eve. Afterward, Peter sees the city’s mayor at the television station. He is prevented from talking to him by Jack Hardemeyer, the mayor’s assistant, who informs him that it would hurt the mayor’s image to be seen conversing with a “fraud.” At the Manhattan Museum of Art, Dana restores an old painting when her boss, Dr. Janosz Poha, a tiny man with a thick Slavic accent, installs a portrait of “Vigo the Carpathian,” a sixteenth century warlord. Dana informs Poha that she is leaving the museum to return to playing cello with the symphony and turns down his offer to go out for drinks. Both are unaware that the Vigo painting is moving. That night, Peter visits Ray at his occult bookstore and bullies him into revealing Dana’s problem. The next morning, over Egon’s protests, he accompanies them to Dana’s apartment. As Ray and Egon examine Oscar, Peter grills Dana on her recent divorce and tells her she should have married him instead. Dana reminds him that whenever she mentioned marriage, Peter would fall asleep. Outside, Egon’s instruments indicate a large supernatural disturbance below the pavement. That night, the trio, accompanied by Winston, disguise themselves as city workers and jackhammer down to an abandoned airshaft. Ray is lowered down and discovers a pneumatic transit line tunnel full of ectoplasmic “slime.” The police arrive just as the slime forms the shape of a hand and grabs at Ray’s leg. Hearing Ray’s screams, Peter presses the winches’ up switch. As Ray ascends, his foot hits a pipe, causing a small explosion that blows up an electrical cable, pitching the city into darkness. Meanwhile, Poha restores the warlord’s portrait when lightning shoots from its eyes and strikes the little man. Vigo steps out of the painting, demanding that Poha find him a baby he can possess. Poha goes to Dana’s apartment, claiming he was worried about her safety during the blackout. She refuses to let him in but as he walks away, light beams emit from his eyes and he looks through the walls to find Oscar. The next day, the Ghostbusters are brought before Judge Stephen Wexler, who refuses to hear any mention of the supernatural in his court. Louis Tully, an accountant and night school law graduate, offers the defense that he once was turned into a dog and the Ghostbusters brought him back. Wexler breaks into a hostile diatribe about them being frauds, causing a slime sample to react by exploding. The ghosts of the Scoleri brothers, two men Wexler sentenced to the electric chair, emerge. Wexler rescinds the injunction and drops all charges, allowing the Ghostbusters to capture the Scoleris in a detainment unit. The Ghostbusters are back in business and make a fortune catching spirits. However, Egon and Ray determine that the slime, a psycho-reactive substance that feeds off emotions, is growing. They pour a sample into a toaster, play pop music and watch it dance, proving it can animate objects. A few nights later, Dana is bathing Oscar when slime bubbles up from the bathtub drain and tries to eat her. She seeks safety at Peter’s apartment. The next morning, Peter, Ray, Egon and Winston go to the art museum to examine the Vigo portrait. As Peter photographs the painting, Egon explains that Vigo was a homicidal tyrant who used the dark arts to terrorize his kingdom until his subjects murdered him. Later, while examining the pictures, Ray and Egon discover an image of the slime river Ray saw in the subway. The photographs burst into flames, igniting the room. The door slams shut, but Winston smashes it down with a fire extinguisher and puts out the flames. They rush over to Peter’s apartment, but he refuses to help search the sewer because he has a date with Dana. Instead, Peter entrusts Oscar to Louis and Janine Melnitz, the Ghostbusters’ secretary, and leaves to celebrate New Year’s Eve. The other three Ghostbusters go underground and are confronted by an illusion of severed heads on pikes and a ghost train that runs over Winston. They find the river of slime and Winston drops a line to measure its depth, but is yanked into the goo and swept downstream. Ray and Egon dive in after him and all three are flushed out a manhole cover in front of the museum. Ray and Winston break into a fistfight, but Egon stops them by explaining the slime is amplified by their negative emotions. They strip down to their undergarments and rush into the restaurant where Dana and Peter are dining to tell them of their discovery. When the police are called, Egon demands to see the mayor. They tell the mayor he must warn the city to stop being negative, but the politician declares it is every New Yorker’s "God-given right" to be rude. When he leaves, Hardemeyer calls the police and has the Ghostbusters thrown into a mental institution. Meanwhile, Dana returns to Peter’s apartment to discover Louis and Janine in an intimate embrace. Feeling a chill, Dana goes into the bedroom to find it empty. She looks out the window and sees Oscar walking on the ledge. A ghostly Poha, under the possession of Vigo and dressed like an evil nanny, flies by and grabs Oscar. Dana rushes to the museum. After she enters, the building is covered in slime. She finds Oscar laid out before the portrait of Vigo surrounded by candles. Poha appears and tells her Vigo will be reborn in Oscar's body at the stroke of midnight. Meanwhile, the slime releases thousands of ghosts, wreaking havoc throughout the city. Learning Hardemeyer had the Ghostbusters committed, the mayor fires him before going to the window to see the sun swallowed by a large black hole. Once released, the Ghostbusters rush to the museum, but their proton packs fail to free the slime-encrusted building. Egon explains that the slime is also activated by good emotions. Needing a symbol of goodwill, the team rushes to the Statue of Liberty and slime its interior. They blast the song "(Your Love Keeps Lifting Me) Higher and Higher," causing the slime to animate the statue. To the crowd’s ecstatic applause, they guide Lady Liberty though the city to the museum. Just as Dana snatches Oscar to safety, they smash a skylight and rappel into the chamber, where they slime Poha and comfort Dana’s concerns by explaining the slime is charged with positive energy and the little man will wake up refreshed. As Vigo emerges from the portrait, a cable wraps around Dana and Peter places Oscar in an empty crate. He yells for the Ghostbusters to shoot, but their photon guns are useless against the warlord, who counters with a force field that paralyzes them as Vigo feeds on Oscar’s life force. Outside, Louis appears wearing Egon's spare Ghostbuster uniform and aims his proton pack at the slime as bells signal the New Year and the crowd sings “Auld Lang Syne.” The positive energy weakens Vigo and he is sucked back into the painting. However, the Carpathian possesses Ray, and Peter orders the others to shoot the painting. The blast knocks Vigo out of Ray and into the portrait, just as Louis fires at the slime from outside. The slime explodes, the hole in the sky disappears, and the crowd swarms Louis as their savior. Inside, Peter and Dana kiss as Poha and Ray, covered with feel-good slime, express love for each other. Winston breaks them up, showing that the portrait now depicts the four Ghostbusters surrounding Oscar wearing togas and halos. They then walk out to receive accolades from the crowd.