The members have gone their separate ways except for Egon Spengler, who still lives in the firehouse, monitors the containment unit, takes care of Slimer, furthers his education, and teaches a class on the paranormal at a local college.

When ghosts begin to reappear, Egon is forced to recruit four students as the new Ghostbusters: Kylie Griffin, a goth genius and expert on occultism; Eduardo Rivera, a cynical Latino slacker; Garrett Miller, a young wheelchair athlete; and Roland Jackson, a studious African-American machinery whiz.

A supernatural comedy, following the trend set by its predecessor, it has an updated, darker feel exemplified by a gritty, punk-inspired variation of Ray Parker Jr.'s song "Ghostbusters" as its opening theme.

Showrunner Bob Higgins told Ability that the decision to create a new Ghostbusters was made by the studio, which hoped to reinvigorate a lucrative franchise.

"[9] The show's creators decided "to put together a team of misfits in a way, people that you would not necessarily associate with being superheroes on television"; Eduardo is a slacker, Roland is a "square," and Kylie is moody and sarcastic.

"[12] During production, Lucy/Garrett was bland until producer Jeff Kline suggested putting the character in a wheelchair; Higgins said that this made Garrett more interesting to write, as he was now "one of these guys that takes what he is given and makes the best of it and lives up to any potential that he has."

[13][14][6] Other elements were changed during production: Egon replaced Janine as the teacher, Slimer lost a goblin sidekick called Gnat, and Garrett was originally Lucas.

Maurice LaMarche was brought back to voice Egon Spengler, but Frank Welker and Laura Summer did not return as Slimer and Janine.

Several years after The Real Ghostbusters ended, there is a lull in supernatural activity in New York City and the team has gone their separate ways.

With Achira spreading disease through the possessed Kylie, the infected Egon helps train and equip the recruits for battle.

The series' failure, blamed by its showrunners on poor US scheduling and the decline of non-educational children's syndication in favor of networks such as Fox Kids and Kids' WB and cable channels (although some American stations carried the series in the 3:00–5:00 pm after-school slot), was seen by SFX as demonstrating that "the appeal of Ghostbusters was only partially the concept, and that it's the characters we love above all must be a sobering thought for anyone charged with rebooting Ghostbusters again."

The series was also noted for aiming at "a slightly more adolescent audience with a tougher edge," "clearly intended to test the boundaries of child-friendly horror."