A librarian at the New York Public Library is reshelving books, a task which takes her into an abandoned basement section. While down there, she begins to notice odd things happening, including books moving from shelf to shelf without anyone visibly moving them. As she walks past a card catalogue, the drawers open of their own power and the cards inside violently scatter across the room. Panicking, she flees deeper into the stacks, until she sees something that causes her to scream in terror and her hair to stand on end...
At the parapsychology department of Columbia University, Dr. Peter Venkman is performing an experiment on 'the effects of negative reinforcement on psychic ability' with two students, which primarily involves administering electric shocks to a hapless geeky male student while flirting with an attractive female student. After the male student storms off following one too many shocks, Venkman's attempts to seduce the female student are thwarted when his excitable colleague Dr. Ray Stanz barges into their office and informs Venkman of the ghost sighting at the Public Library. Reluctantly, Venkman allows himself to be dragged by Ray to investigate the event, where they meet with their colleague, Dr. Egon Spengler. After interviewing the traumatised librarian, Venkman, Ray and Egon make their way into the basement, where they eventually encounter the spectral apparition of a woman, apparently a librarian. Having not anticipated an actual encounter with a ghost, the three scientists are unsuccessful in attempting to communicate; Venkman's initial attempts at conversation are rebuked by the ghost, while Ray's suggestion that they attempt to grab her results in the ghost morphing into a terrifying demon-like creature, causing the scientists to flee.
As a result of their encounter, Egon announces that according to his readings, it is hypothetically possibly to capture and contain a ghost. Unfortunately for the three, when they arrive back at their laboratory at Columbia they discover that it is being emptied by Yeager, the university dean, who informs them that the university is terminating their research grant and kicking them off campus owing to their disreputable research methods and reputation. While Egon and Ray are despondent, Venkman suggests that they use Egon's research to build a ghost-containment unit and go into business hunting and capturing ghosts. Advertising themselves as the "Ghostbusters", the three rent a dilapidated firehouse, purchase a decommissioned ambulance and hire Janine Melnitz to work as their secretary, but do not attract any business.
Meanwhile, Dana Barrett, a concert cellist, returns home to her apartment at Central Park West after a rehearsal. After an awkward encounter with her neighbour Louis Tully, who nurses an unrequited crush on her, she begins to put away groceries only to watch in astonishment as a carton of eggs begin cooking themselves on her kitchen counter. After hearing an inhuman growling from her refrigerator, upon opening the door she finds that the inside has been transformed into a portal into a bizarre alternate dimension populated by terrifying dog-like creatures, one of whom bellows "Zuul..." at her. Fleeing her apartment, she turns to the Ghostbusters for help having happened to catch their commercial. Instantly attracted to her, Venkman agrees to return to her apartment under the pretext of investigating the matter, but by the time they arrive there is no sign of any paranormal activity. Frustrated by Venkman's skeptical attitude to her story and his attempts to seduce her, Dana kicks him out of her apartment.
The Ghostbusters are on the edge of bankruptcy when they receive a call from the glamorous Sedgewick Hotel begging for their services. Guests and staff have reported seeing a gluttonous green spectre made of slime floating around the corridors, and the concierge wants it removed before it threatens the hotel's business. Armed with nuclear-powered 'proton packs' and ghost-traps, the Ghostbusters hunt 'Slimer' through the hotel corridors; during their hunt, Egon warns the others not to cross the streams of the proton-packs, suggesting potentially devastating consequences. After Venkman encounters Slimer and is 'slimed', the Ghostbusters corner it in the hotel's ballroom. The Ghostbusters eventually manage to contain and trap the ghost, although not without causing much property damage and destroying a priceless chandelier in the process. Nevertheless, the successful ghost-hunt at the Sedgewick Hotel sees the Ghostbusters quickly become local celebrities. The Ghostbusters' fame also coincides with a dramatic spike in ghost sightings and paranormal activity throughout New York City, and they are soon utterly overworked.
In order to cope, the three Ghostbusters hire a fourth member, Winston Zeddemore. They are also visited by Walter Peck, a pompous representative of the Environmental Protection Agency, who is skeptical of the Ghostbusters' work and demands to see the containment facilities. Angered by Peck's manner, Venkman gets into an argument with him and refuses to allow him access. Owing to the recent paranormal activity, the containment unit is getting increasingly full and unstable, leading Egon to speculate that a major paranormal event is on the horizon.
Still infatuated with Dana, Venkman does research on her paranormal encounter and discovers that Zuul is the name of an ancient Sumerian demigod who in turn was the minion of a greater entity called Gozer. Increasingly charmed by Venkman, Dana agrees to meet him for a date, but on the night that they are to meet she is attacked in her apartment by one of the dog-like demons she saw in her refrigerator. Another creature attacks Louis Tully at a party, sending him fleeing into Central Park where he is cornered and dragged off screaming. Arriving at Dana's apartment for their date, Venkman discovers that she has been possessed by Zuul and is calling herself 'the Gatekeeper'. Mistaking Venkman for an entity she calls 'the Keymaster', Dana/Zuul makes several attempts to seduce Venkman, who rebuffs her each time and tranquillizes her after watching her growl and snarl like a demon and levitate four feet over her bed. Louis Tully, meanwhile, has been possessed by a creature calling itself Vinz Clortho, 'the Keymaster', and wanders the streets of New York raving about the coming apocalypse until he is picked up by the police, who in turn take him to the Ghostbusters.
The next morning, Walter Peck arrives with a court order that demands that the Ghostbusters shut off the power to the containment grid and cease business operations. Arrogantly dismissing both Egon's pleas not to shut down the system and the electrical engineer's hesitation at meddling with the complicated set-up, Peck has the power shut down — at which point the containment grid explodes, freeing the trapped ghosts and triggering major paranormal chaos throughout the city. Peck blames the Ghostbusters and has them arrested, while Louis/Vinz escapes in the confusion. In jail, the Ghostbusters consult architectural records of Dana's building and discover that the building's architect was Ivo Shandor, a mad doctor and cult leader who, following World War One, decided that society was "too sick to survive". Consequently, he and his cult performed sacrifices on the roof to summon Gozer, the building having been designed to absorb paranormal energy and provide a doorway for Gozer to enter this universe. At Central Park West, Louis/Vinz arrives and finally meets and shares a passionate embrace with Dana/Zuul.
The Ghostbusters are ordered to be released by the Mayor, who consults with them and Peck following the chaos that is erupting throughout the city. Although Peck argues that the Ghostbusters are con artists, the Ghostbusters manage to convince the Mayor that the city and the world are facing an apocalyptic threat — and that by hiring the Ghostbusters to solve it, the Mayor will practically guarantee his re-election. Convinced, the Mayor dismisses Peck and arranges for a police and National Guard escort to take the Ghostbusters to the building, where they are cheered by a crowd that has gathered around the building in anticipation of the end of the world. The Ghostbusters enter the building and make their way to the ruins of Dana's apartment, where they discover a staircase leading up to a temple on the building's roof. There, they watch as Dana/Zuul and Louis/Vinz open a massive doorway and are transformed into demons and a near-naked woman with red eyes crosses over from the alternate dimension; Egon identifies her as Gozer.
After Ray's attempts to invoke bureaucracy to convince Gozer to return to her dimension of origin fail, Gozer attacks them. After the Ghostbusters use their proton-packs on her, Gozer appears to dissipate, but a booming voice demands that the Ghostbusters "choose the form of the destructor". Realising that Gozer will take on the appearance of whatever the Ghostbusters think of and use it to destroy the world, Venkman orders them not to think of anything, but unfortunately Ray —trying to think of something that could not possibly be harmful — has already made the choice. The Ghostbusters watch in astonishment as a giant version of the Stay Puft Marshmallow Man, a popular corporate logo, materialises in the city and strides towards the building; Ray had associated with Stay Puft with eating marshmallows around the campfire in his youth, and Gozer has taken on its form.
After blasting Gozer's new form with the proton-packs does not work, in desperation Egon suggests that they cross the streams of the proton-packs in order to create a huge surge of energy that will close the doorway to Gozer's realm. As they do so, the roof of the building is destroyed in a fiery explosion that incinerates Gozer and its minions, but the Ghostbusters manage to find shelter and survive. Although the outer forms of the minions are destroyed, both Dana and Louis have survived within the shells and are freed from possession, having no memory of what has occurred. Dana and Venkman kiss, and having saved the city and the world the Ghostbusters return to the street to a hero's reception from the crowd — but as they drive off, no one notices that 'Slimer' is once again roaming free...
