"The Real" was added to the show's title after a legal dispute with Filmation, which owned the unrelated Ghost Busters live-action property and was simultaneously producing its own cartoon revamp of that series.

An early four-minute promo pilot was produced but never aired in full; in it the Ghostbusters wore beige jumpsuits like in the film and Peter Venkman's character design closely resembled actor Bill Murray, unlike the color-coded jumpsuits later used in the final show.

Maurice LaMarche was asked not to impersonate Harold Ramis when auditioning for Egon Spengler, but he did it anyway and won the role regardless.

Bill Murray off-handedly remarked to producers that Lorenzo Music's voice for Peter Venkman sounded like Garfield, since Music also voiced that character at the time; Murray himself later went on to voice Garfield in the 2000s films after Music's death in 2001.

Dave Coulier took over as Peter Venkman starting in season three because producer Joe Medjuck, who had also worked on the original film, wanted the character to sound more like Bill Murray.

Ernie Hudson was the only actor from the films to audition for his own character (Winston Zeddemore) in the animated series, but the role went instead to Arsenio Hall and later Buster Jones.

The voice cast always recorded their dialogue together in Los Angeles rather than separately, which was unusual for animation production at the time; the finished audio, storyboards, backgrounds and character designs were then shipped to Japanese studios for animation, with South Korean studios also used in the final two seasons.

Many character redesigns in season two, including softening Janine Melnitz's personality, hairstyle and outfits, were driven by ABC hiring a consulting firm called Q5 to boost ratings, a move that writers J. Michael Straczynski and Michael Reaves publicly criticized as racist and sexist, citing the decision to make Winston, the only main African-American character, simply "the hands" who drives the car.

The season 1 episode "Take Two" features the Ghostbusters visiting a Hollywood movie set that is revealed to be the making of the original 1984 Ghostbusters film.

The episode "Citizen Ghost" serves as a flashback explaining how Slimer changed from a villainous ghost into the team's resident friend, and how their uniforms and containment unit were redesigned, tying directly into the events following the first film.

The first season holds a 100% approval rating on Rotten Tomatoes based on five reviews.