A psi energy pulse emanates from the Gozer exhibit at the Museum of Natural History, engulfing New York City and increasing supernatural activity. The pulse frees Slimer from the Ghostbusters' headquarters, and the Ghostbusters and the Rookie pursue it to the Sedgewick Hotel, where Slimer was first captured.[24][27] They find that the hotel is haunted by dozens of ghosts and that the Destructor Form of Gozer, the Stay-Puft Marshmallow Man, has returned and is wreaking havoc throughout the city.[28] Under Ray's guidance, the Rookie destroys Stay-Puft, with the Ghostbusters noting that he was pursuing Sumerian expert Dr. Ilyssa Selwyn.
Another haunting at the New York Public Library draws the team into a confrontation with the restless spirit of the librarian, Dr. Eleanor Twitty (the first ghost encountered by the Ghostbusters in the first film). They learn that Dr. Twitty had been murdered by the philologist Edmund Hoover (a Gozerian cult leader known as the Collector) over a rare book, the Gozerian Codex. After capturing Dr. Twitty, a portal opens to an afterlife dimension referred to by the Ghostbusters as the Ghost World. The Ghostbusters travel through the portal and encounter the spirits of Gozerian cultists. These spirits include Hoover, reborn as Sumerian demi-god Azetlor the Destroyer, whom the Ghostbusters defeat. A recurring symbol the team sees in these haunted locations is revealed to be a mandala representing a spiritual labyrinth running throughout the city, with major nodes positioned toward the library, museum, hotel, and in the Hudson River.[29][30] The mandala is powered by the ghosts that are drawn into it, increasing in power as they pass through each node, before being fed into the core to power a Destructor Form like Gozer's. The energy merges the Ghost World into the mortal realm, which could result in a disaster of apocalyptic proportions.[31]
Mayor Jock Mulligan places the team's nemesis, Walter Peck, in charge over the Ghostbusters' operations. The Ghostbusters cleanse the museum and hotel and defeat two cult leaders, the Chairman (Cornelius Wellesly) and the Spider-Witch (Evelyn Lewis). At the final node in the Hudson River, the team locates Ivo Shandor's island mansion rising from the water, and discovers that Ilyssa is the occultist's descendant.[32][33] It was Ilyssa's presence that triggered the mandala after Peck recommended her to curate the Gozer exhibit, leading the Ghostbusters to suspect that Shandor's spirit has possessed Peck to orchestrate events. They also discover machines built by the cultists pumping various colors of ectoplasmic slime into tunnels beneath the city, including the pink "mood slime" from their prior adventure, turning the municipality into a supernatural hotspot that allowed the spirit of Vigo the Carpathian to empower himself.[34] The Ghostbusters disable the pumps and destroy the creature producing the slime, closing the last node and sealing the mandala, trapping its accumulated energies.[35]
Returning to their headquarters, the Ghostbusters find that Ilyssa had been abducted and the team's ecto-containment unit had been shut down again, releasing their supernatural captives. Because the team disabled the mandala, the cultists retaliate by using the Ghostbusters' captives to provide an alternate energy for their Supreme Destructor and need Ilyssa for the ritual.[36] The Ghostbusters battle their way to the center of a mausoleum emerging in Central Park. Like Shandor's building on Central Park West where they defeated Gozer, it is also a gateway between dimensions. They discover that Ilyssa and Peck are both prisoners, and that Shandor has in fact possessed Mayor Mulligan while using Peck as his decoy and pawn to hinder their operations.[37][38] Seeing his god defeated by the Ghostbusters twice, Shandor decided to usurp Gozer's position and deal with them himself, having become godlike after making pacts with the Gozerian pantheon. Because Shandor is already dead, he would need a living blood relative (Ilyssa) nearby for his schemes to work. The Ghostbusters exorcise Shandor from the Mayor but are dragged into the Ghost World, where they battle Shandor's Destructor Form, a being called the Architect hell-bent on ruling a post-apocalyptic world as its god. Just as they had done to defeat Gozer, the Ghostbusters cross their proton streams, causing an explosion that destroys Shandor's avatar and sends the team home. They escape the collapsing mausoleum with Ilyssa, Peck, and Mayor Mulligan.[39][40]
During the credits, the four original Ghostbusters realize they are overstaffed, but offer the Rookie a position as the head of a yet-to-be-opened Ghostbusters franchise in another location.[41]
