A trio of scientists become a team of ghostbusters when New York City starts to become infested with ghosts.
At the New York Public Library, a Librarian is collecting books to re-shelf. She goes down into the basement and as she passes bookcases, books float from one bookcase to another. The card catalog drawers open by themselves and the cards go flying into the air and the Librarian starts to run away. As she turns a corner she sees Library Ghost and screams. Dr. Peter Venkman is conducting a research project with a Male Student and a Female Student. The Students take turns guessing the designs on the back of a set of cards Peter holds up and he zaps them if they guess incorrectly. While the Male Student gets zapped even if he guesses correctly, the Female Student is never zapped by Peter. The Male Student finally gets tired of being zapped and walks out. As Peter is flirting with the Female Student, Dr. Raymond Stantz runs excitedly into the office and tells Peter a ghost was spotted at the New York library and they have to go investigate it. They meet up with Dr. Egon Spengler and then speak with the Library Administrator. They interview the Librarian and then go down into the basement. They find the card catalog drawers full of ectoplasmic residue, which Egon has Peter collect a sample of. They find the Library Ghost and their initial plan is to talk with the ghost, but it shushes Peter. They then decide to charge at it, but it transforms into an even scarier form and they run away.
They return to the university and Egon tells the others he thinks they may be able to build a device that catches ghosts. They find their office being cleaned out and Dean Yeager tells them they are all fired. Peter tells Raymond that he thinks they should go into the business of catching ghosts and Raymond takes a third mortgage out on his inherited home. They look for an office and buy an old firehouse shown to them by a Real Estate Woman. As Dana Barrett is walking to her apartment, Louis Tully invites her to his apartment to have some low sodium mineral water. She goes into her apartment and sees a commercial for the Ghostbusters. As she is putting her groceries away, her egg carton lid pops open and the eggs start to cook on the counter. She hears a growling noise from her fridge and opens it up and a large dog like creature says Zuul. Raymond drives an old hearse he bought used to the office. Peter asks Janine Melnitz if they have had any customers and then insults her in frustration when she repeatedly tells him no. Dana walks into their office and Peter interviews her about the incident at her apartment while Egon and Raymond scan her with machines. Raymond offers to go to the Hall of Records to check on construction plans for the building, Egon offers to look up the name Zuul in Tobin's Spirit Guide, while Peter offers to take Dana to her apartment to check it out. Peter and Dana go to her apartment and he uses a portable sniffer as they walk around the apartment. They go into the kitchen, but the fridge is normal. Peter tries to ask Dana out on a date, but she rejects him.
The Ghostbusters get a call and Janine presses the emergency button. They drive to the Sedgewick Hotel and the Hotel Manager tells them about the ghost on the 12th floor. They walk to the elevator where Man at Elevator comments on their suits and they tell him they are exterminators. They exit onto the 12th floor and Raymond and Egon shoot their blasters at Chambermaid who turns around the corner. They apologize to her and then split up. Raymond sees Slimer and fires his prositron collider at it, but misses. As Peter is walking, Slimer sees him and charges at him, sliming him as it passes through him. Egon radios Raymond and tells him Slimer went into the ballroom and Raymond and Peter head in that direction. Raymond tells Hotel Manager to wait outside as he, Egon and Peter close the ballroom doors. They see Slimer and shoot at it, but miss, destroying a large chandelier in the process. Egon warns them not to cross their blaster streams and they continue to shoot at Slimer, causing increasing damage to the ballroom. Outside, Hotel Manager assures Mrs. Van Hoffman that the ballroom will be ready in time for her group's event. They eventually catch Slimer and at first the Hotel Manager refuses to pay the bill, until the Ghostbusters threaten to release Slimer. Roger Grimsby reports that there is increasing talk of paranormal activity on the East Coast. TV Reporter tells viewers about a story his grandmother used to tell about ghosts. The Ghostbusters get increasingly more work and notoriety. Larry King has a show about the Ghostbusters and if they are real or fake. Casey Kasem updates listeners to where the last Ghostbusters catch was at. At the location of one of their catches, Peter tells Reporters about their work. Joe Franklin interviews Raymond and asks him how Elvis is doing.
Raymond has a dream where he receives oral sex from Dream Ghost. Winston Zeddmore answers a job advertisement in the paper and is interviewed by Janine. Raymond and Peter walk in and Raymond hires him on the spot. Dana walks out of the orchestra building with Violinist and sees Peter standing outside. Dana asks Peter if he has any information about her case and he gives her background information on Zuul. He invites her out on a date to provide her with more information and she accepts. Walter Peck goes to the Ghostbusters headquarters and asks Peter questions about the Ghosbusters' business. When Peter refuses to allow Peck to see the storage facilities, Peck threatens to come back with a court order. As Raymond is showing the ins and outs of the business, Egon tells them he is worried about the amount of paranormal activity. At Dana's building, the giant dog statues crack open. Dana goes into her apartment and as she sits down, she is grabbed by demonic arms that come out of the couch and she is pulled towards the fridge and an incarnation of Zuul as the dog statue. Woman at Party asks Louis if he has Tylenol and he tells her he gets the generic brand to save money. Tall Woman at Party tells Louis she is going to leave and he suggests they dance and then stares at her chest as they dance. Ted Fleming and Annette Fleming arrive at the party and after Louis throws their coats into the closet, Vinz Clortho manifested as the dog statue breaks out of the closet and chases him. Louis runs out of his apartment and takes the elevator as Louis's Neighbor sees Vin Clortho and runs back inside her apartment. Louis runs out of the building and Doorman tells people walking up that Louis said a bear was in his apartment. Louis runs to the Tavern on the Green and is attacked by Vin Clortho.
Peter walks up to Dana's apartment building and Policeman at Apartment tells him someone brought a puma to a party and it went berserk. He goes to Dana's apartment and notices her exhibiting odd behavior. Louis, now possessed, looks for the gatekeeper and after talking to a horse and being interrupted by Coachman, yells at the Coachman that he will perish in flames. Police Sergeant goes to Ghostbusters' headquarters and drops off Louis. Egon does a scan of Louis and Louis provides the background of Vin Clortho and Gozer. Peter calls Egon and tells him about Dana and Egon tells him about Louis. Raymond and Winston discuss the Bible and Winston has the theory that the dead are rising from the grave. A group of vehicles pull up to Ghostbusters headquarters and Peck walks into the building with a Police Captain and a Con Edison Man. Janine tries to stop them, but they barge their way downstairs. Peck orders the Con Edison Man to shut down all the equipment, but Egon warns them against it. Peck orders the Con Edison Man to shut it down and after he does, alarms start blaring. Dana wakes up as a massive cloud and ray of light breaks through the headquarters and goes into the sky. Peck tells the Police Captain that he wants the Ghostbusters arrested. A ghost goes into the tail pipe of a taxi cab and after Businessman in Cab orders the driver not to doddle, the ghost cab driver drives wildly in traffic. Slimer bursts from a Hot Dog Vendor's cart with a mouth full of hot dogs.
While in prison, Egon goes over the building plans of Dana and Louis' apartment with the other Ghostbusters and Raymond tells them the building is an antenna built to absorb spiritual turbulence. Egon tells them the builder was Ivo Shandor who started a Gozer cult. Jail Guard brings the Ghostbusters to see the Mayor. Louis opens Dana's door and they kiss and walks towards the roof of their building. The Mayor's Aide tells the Mayor, the Ghostbusters are present. Peck is also brought into the office and the Mayor questions the Ghostbusters and Peck about what happened. The Fire Commissioner tells the Mayor he has never seen any combustion like that which came out of Ghostbusters headquarters and the Police Commissioner says the walls of the 53rd Police Precinct were bleeding. The Archbishop walks into the Mayor's office and tells him he thinks what is happening is a sign from God. Peter wins the Mayor over by mentioning that if they are wrong nothing happens, but if the Ghostbusters can stop it, then the Mayor's decision will have saved the lives of millions of registered voters. The Mayor then sides with the Ghostbusters. The Ghostbusters are brought to Dana and Louis' apartment building and they are almost swallowed when the ground rips open. The Ghostbusters slowly make their way to the roof. Dana and Louis are transformed into the dog like forms of Zuul and Vinz Clortho. Gozer walks out from a sky temple/portal and Raymond approaches it and asks it to return to its own realm. Gozer asks if Raymond is a god, and when Raymond responds in the negative, Gozer tries to kills the Ghostbusters. The Ghostbusters turn on their proton weapons and fire at Gozer, but she easily jumps away. They fire at her again and she disappears. Gozer's voice calls out that Volguus Zildrohar the Traveler has come and they must choose their form of the destructor. Raymond imagines the image of the Stay Puft Marshmallow Man and a giant Stay Puft Marshmallow Man appears and starts to destroy the city. The Ghostbusters fire their weapons at it and catches it on fire, but continues to walk towards them. Egon suggests to cross the streams and fire them at the dimensional portal and after they do, the portal disappears and the Stay Puft Marshamallow Man explodes, covering everyone in marshmallow. Peter initially thinks Dana is dead, but discovers the dog form was only a shell and they free her and Louis. The Ghostbusters, Dana and Louis walk out of the building and are cheered by the crowd.