According to Parker, he was approached by the film's producers to create a theme song for the film, though he only had a few days to do so and the film's title seemed impossible to include in any lyrics. However, when watching television late at night, Parker saw a cheap commercial for a local service that reminded him that the film had a similar commercial featured for the fictional business. This inspired him to write the song as a pseudo-advertising jingle that the business could have commissioned as a promotion.
Lindsey Buckingham claims to have been approached to write the Ghostbusters theme based on his successful contribution to Harold Ramis's National Lampoon's Vacation (the song "Holiday Road"). He turned down the opportunity as he did not want to be known as a soundtrack artist. He mentions this on the "Words & Music" interview disc.
The music video for the song was directed by the same director as the Ghostbusters film, Ivan Reitman, and produced by Jeffrey Abelson. It features a young woman, played by actress Cindy Harrell, who is haunted by a ghost portrayed by Parker, roaming a nearly all-black house interior with vibrant neon designs outlining the sparse architectural and industrial features until the woman finally calls the service. It also contains footage from the film and features cameos from many celebrities of the day, including Chevy Chase, Irene Cara, John Candy, Melissa Gilbert, Ollie E. Brown, Jeffrey Tambor, George Wendt, Al Franken, Danny DeVito, Carly Simon, Peter Falk, and Teri Garr; all of whom exclaim the song's "Ghostbusters!" refrain when shown. Chase appears again after Garr, but chokes on his cigarette when he tries to exclaim "Ghostbusters!"; Franken also pops up in the house before the separately framed cameos begin.
The video concludes with Parker and the stars of the film, in full Ghostbuster costume, dancing down the streets of New York City. The crew closed down Times Square to film the scene. The Ghostbusters also perform the same dance in the closing credits to the Real Ghostbusters cartoon series as well as in a trailer for the 2009 Ghostbusters video game.
When the theme song of Ghostbusters was released, Huey Lewis sued Columbia Pictures and Ray Parker Jr. for plagiarism, stating that Parker's song was too similar to Lewis's "I Want a New Drug." Lewis had been approached to compose the main theme song for the film. The three parties settled out of court. Details of the settlement (specifically, that Columbia Pictures paid Lewis a settlement) remained confidential until 2001, when Lewis commented on the payment in an episode of VH1's Behind the Music. Parker subsequently sued Lewis for breaching confidentiality.
The sketch comedy series Key & Peele parodied the song in a 2015 sketch in which Ray Parker Jr. advertises a CD box set, Ray Parker Jr.'s Greatest Hits, consisting of theme songs he wrote and unsuccessfully submitted for other movies, all done with the combination of literal lyrics and uptempo music of "Ghostbusters".
In 2014, Nickelodeon parodied the song to promote the premiere of the Bubble Guppies episodes "Bubble Scrubbies" and "Swimtastic Check Up".
The slightly longer instrumental version contains two extra sections with additional instrumentation, which aren't present in the vocal version. One of these sections gives the song a proper ending, unlike the vocal version which fades out.
The song's music video begins with Sigourney Weaver and Annie Potts climbing out of a limousine in front of a large crowd. They are accompanied by Run–D.M.C. and Jam Master Jay dressed in the standard beige Ghostbusters' uniform, who then perform the song on stage to a packed audience for the remainder of the video, intercut with clips from the film. Bill Murray, Dan Aykroyd, and Ernie Hudson also make cameos as security personnel.
The Rasmus official website described the cover as:
The idea of having to Ray Parker's "Ghostbusters" in a different interpretation [on the EP3rd] came about when the boys joked and shouted "Who you gonna call? Ghostbusters" to each other. This song is the only cover song Rasmus ever made. All other songs are in their own production.
"Ghostbusters (I'm Not Afraid)", a version of the song by American rock band Fall Out Boy, featuring hip hop recording artist Missy Elliott, was released on June 23, 2016, off the film's remake motion picture original soundtrack, which was released on July 15, 2016.
Another cover version of the song appears on the soundtrack album to the Ghostbusters reboot film. Unlike the very different song first released by Fall Out Boy and Missy Elliott, Walk the Moon's version is much closer to the original song.
In 2018, Automobile Dacia, which is usual to release television spots with cars and people singing as they see them, released a spot for one of its models, the Duster, accompanied by the song, in an instrumental version, but with people in funny disguises singing "Go, Duster!" when in the standard song the chorus says "Ghostbusters!".