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Five years after their near destruction of New York City after which they were sued until bankrupt and a restaining order placed on them that prevents them from working as Ghostbusters, Doctors Peter Venkman (Bill Murray), Ray Stantz (Dan Aykroyd), Egon Spengler (Harold Ramis), and Winston Zeddemore (Ernie Hudson), aided by their attorney Louis Tully (Rick Moranis), finally convince a judge to lift the restraining order. Voila! The Ghostbusters are back in business and just in the nick of time as a massive river of "mood slime" is flowing through the abandoned Pneumatic Transit tunnels under Manhattan, and it appears that an ancient Carpathian sorcerer, Vigo Von Homburg Deutschendorf, (Wilhelm von Homburg) wants to possess Dana Barrett's (Sigourney Weaver) 8-month-old baby Oscar (William T. Deutschendorf and Henry J. Deutschendorf II).

Ghostbusters II is the sequel to Biệt Đội Săn Ma (1984), both of which were written by co-stars Dan Aykroyd and Harold Ramis. Ghostbusters II was subsequently novelized in 1989 by American scifi/mystery writer Ed Naha.

"Mood slime" is pictured as pink ectoplasm and described as a psychoreactive substance that responds to human emotional states. In short, it feeds on bad vibes. It was not explicitly mentioned what the slime was made of. They do, however, imply the slime was "brought to life" by Vigo and powered by the general bad vibes of the New Yorkers. You could take from this that the slime was either created by "ghost-power" or that the slime started from something very small and absorbed various elements from its environment. It was eventually established in the 2009 video game Ghostbusters: The Video Game (2009) that the slime was manufactured by a contraption created by Ivo Shandor, the Gozer worshiper.

Dana only mentions that Oscar's father left her to play with orchestras in Europe. Fans have speculated that the father is Timothy Carhart's character from the original movie, the violinist that Venkman calls "the stiff".

This isn't made clear in the movie. It may be that, through his father, Oscar is a member of some family or bloodline that makes him a distant relative of Vigo. Or perhaps Dana's experience being possessed in the original film may have somehow made her son ripe for possession himself. Of course, it is actually Janosz who selects Oscar, no doubt due to his feelings for Dana. Vigo simply requests "a child" and it is likely that he would have been just as satisfied with any other baby.

With just four minutes to go until midnight, Dana watches helplessly as Vigo begins his transfer into Oscar's body. Suddenly, the torch-bearing arm of the Statue of Liberty crashes through the skylight, Dana grabs Oscar, interrupting the transfer, and the Ghostbusters rappel down. They shoot positively-charged slime all over Janosz (Peter MacNicol) (who'll wake up feeling like "a million bucks"). Vigo immobilizes Dana and the Ghostbusters and materializes out of the painting. He picks up Oscar and prepares to possess his body. Meanwhile outside, Louis arrives in full ghostbusters attire, and the crowd begins singing "Auld Lang Syne" as he zaps the slime barrier with a proton stream. The positive energy causes the barrier to disintegrate and forces Vigo back into the painting. In desperation, Vigo takes over Ray's body, but the others cover him with positive slime, destroying Vigo. As they revel in all the positive energy, Winston notices that the painting of Vigo has been replaced with a scene showing the four Ghostbusters standing protectively around Oscar.

"(Your Love Keeps Lifting Me) Higher and Higher" written by Jackie Wilson. In the movie it is performed by Howard Huntsberry, though the Jackie Wilson original is heard during the dancing toaster scene.