It was followed by a sequel, Ghostbusters II in 1989, and two animated television series, The Real Ghostbusters (later renamed Slimer! And the Real Ghostbusters) and Extreme Ghostbusters. Ramis, who co-wrote the first two films, has confirmed that a script for a potential third film is being developed by Gene Stupnitsky and Lee Eisenberg, the writing team best known for their work on Curb Your Enthusiasm and the American version of The Office. Ramis told a Chicago Tribune columnist in 2008 that the original films' four main cast members may have minor on-screen roles: "The concept is that the old Ghostbusters would appear in the film in some mentor capacity". The American Film Institute ranked Ghostbusters 28th in its 100 Years... 100 Laughs list of film comedies.

After losing their jobs at Columbia University, a trio of misfit parapsychologists—Peter Venkman, Raymond Stantz, and Egon Spengler—establish their own paranormal exterminator service, "Ghostbusters." The business, operating out of an abandoned fire station (located at 14 N. Moore St. in TriBeCa), gets off to a slow start, but just as they run out of money, the Ghostbusters are contacted by the upscale Sedgewick Hotel to investigate a haunting. At the hotel, they successfully (albeit chaotically) capture their first ghost and deposit him into a "containment unit" of their own design located at the Ghostbusters office. Paranormal activity appears to be on the rise in the city and business skyrockets for the Ghostbusters, who become local celebrities and hire a fourth member, Winston Zeddemore.

The Ghostbusters are hired by a woman named Dana Barrett, whose apartment at 55 Central Park West is haunted by a demonic spirit called Zuul, a demigod worshipped in 6000 BC as a servant to Gozer the Gozerian, a Sumerian shape-shifting god. Venkman, who finds Dana attractive, takes a particular interest in the case, competing for her affection with her socially-inept neighbor Louis Tully. As they look into the matter, Dana is possessed by Zuul, which declares itself "The Gatekeeper". Louis is also discovered to be possessed by a similar demon called Vinz Clortho, "The Keymaster". Both demons speak of the coming of the destructive god Gozer, and the Ghostbusters decide it would be prudent to keep the two separated from each other. However, the next day, the Ghostbusters office is visited by Walter Peck of the EPA, who arrests the team and orders their ghost containment grid shut down, unleashing hundreds of ghosts onto New York City. Freed from the Ghostbusters' protective custody, Louis/Vinz begins making his way toward Dana/Zuul's apartment as the escaped ghosts create havoc throughout the city.

Consulting blueprints of 55 Central Park West, the Ghostbusters learn that it was built by a mad doctor and cult leader named Ivo Shandor, who designed the building to act as a spiritual magnet to summon Gozer and bring about the end of the world. The Ghostbusters are brought to the mayor's office and freed in order to combat the paranormal activity. The Ghostbusters head towards the Shandor Building, arriving at the shrine at the top. They are unable to stop Dana and Louis from transforming into demonic beasts and summoning Gozer, who initially appears as a woman. Briefly subdued by the team, Gozer disappears, though her voice echoes that the "destructor" will follow, taking a form chosen by the team. Venkman explains that this means that whatever they imagine will be manifested as a destroying force, and urges everyone to blank their minds to avoid giving form to the destructor. Rumbling footfalls are heard in the distance, however, and Ray Stantz finally admits that he was unable to keep his mind blank, so he imagined "something that could never, ever possibly destroy us." The destructor arrives in Stantz's chosen form of the giant Stay Puft Marshmallow Man and begins laying waste to the city. Although they manage to light him on fire with their Proton Packs, it only makes him angry and he continues advancing towards the building. To defeat this manifestation of Gozer, the team decides to merge the energy streams of their Proton Packs (which breaks their Number One Rule), and aim at the dimensional portal Gozer came through, at the risk of their own lives. They ultimately follow through with this plan and destroy Stay Puft, who explodes into torrents of melted marshmallow, some of which dumps on Peck below.

The Ghostbusters survive, and Dana and Louis emerge out of the charred remains of their possessors. As they exit the building, the Ghostbusters are met with cheers from the gathered crowd. A dazed Louis is taken away for medical attention while Venkman and Dana kiss as they drive off.

The concept was inspired by Aykroyd's own fascination with the paranormal and it was conceived as a vehicle for himself and friend John Belushi, fellow Saturday Night Live alumnus. The original story, as written by Aykroyd, was very different from what was eventually filmed. In that early version, a group of Ghostbusters travelled through time, space and other dimensions taking on huge ghosts (of which the Stay-Puft Marshmallow Man was just one of many). Also, the Ghostbusters wore S.W.A.T.-like outfits and used wands instead of Proton Packs to fight the ghosts. Ghostbusters storyboards show them wearing riotsquad-type helmets with movable transparent visors. In addition to a similar title, the movie shares the premise of professional "exterminators" on a paranormal mission with The Bowery Boys slapstick comedy Spook Busters (1946, directed by William Beaudine).

Aykroyd pitched his story to director / producer Ivan Reitman, who liked the basic idea but immediately saw the budgetary impossibilities demanded by Aykroyd's first draft. At Reitman's suggestion, the story was given a major overhaul, eventually evolving into the final screenplay which Aykroyd and Ramis hammered out over the course of three weeks in a Martha's Vineyard bomb shelter in May-June 1982. Aykroyd and Ramis initially wrote the script with roles written especially for Belushi, Eddie Murphy and John Candy. However, Belushi died during the writing of the screenplay, and neither Murphy nor Candy would commit to the movie, so Aykroyd and Ramis made some changes and polished a basic, sci-fi-oriented screenplay for their final draft.

In addition to Aykroyd's high-concept basic premise, and Ramis' skill at grounding the fantastic elements with a realistic setting, the film benefits from Bill Murray's semi-improvisational performance as Peter Venkman, the character initially intended for Belushi.

Louis Tully was originally conceived as a conservative man in a business suit played by comedian John Candy, but with Candy unable to commit to the role, it was taken by Rick Moranis, portraying Louis as a geek. Gozer was originally going to appear in the form of Ivo Shandor as a slender, unremarkable man in a suit played by Paul Reubens. In the end, the role was played by Yugoslav model Slavitza Jovan.

Harold Ramis had no intention of acting in any role in the film as he planned on only helping Aykroyd write the screenplay. However, the crew struggled to cast the role of Egon Spengler, even after renowned actors such as Chevy Chase, Michael Keaton, Christopher Walken, John Lithgow, Christopher Lloyd, and Jeff Goldblum were considered. Feeling he knew the character best since he created him, Ramis accepted the role of Egon. He credits this move in revitalizing his acting career, as Ramis had previously focused on off-screen work such as writing and directing.[citation needed]