In New York during 1904, a frantic group of firefighters enters a blazing hotel, only to find a room completely frozen over. One of the firefighters plays a recording of the unusual scene on an old speaker. Fast forward to the present day, the Spengler family—along with Gary Grooberson—is in pursuit of an ice dragon. Phoebe Spengler rides alongside in the Ghostbuster vehicle, successfully capturing the creature with a zapper. Their companions, Podcast and Domingo, recently relocated back to New York City, collaborate with Winston Zeddemore and Ray Stantz, who are seasoned members of the Ghostbusters team. They ultimately manage to trap a ghost lurking in Hell's Kitchen, transforming it into their long-standing adversary, Mayor Walter Peck, who expresses dissatisfaction over the chaos wrought upon his city, threatening to dismantle the Ghostbusters.
Callie Spengler decides that Phoebe, the youngest member, must be removed from active duty until she turns eighteen. Distraught over her exclusion from the team, Phoebe finds solace playing chess with the specter of a girl named Melody, who perished in a previous fire. Meanwhile, at an antique shop, Ray and Podcast encounter a myriad of bizarre “cursed” items, which Podcast examines for supernatural activity. During one investigation, he stumbles upon a horde of mischievous mini-pufts that cause mayhem. Back at the shop, a newcomer, Nadeem Razmaadi, hands them an old orb that he claims is cursed, inherited from his grandmother. Ray identifies the orb as a trap for supernatural entities, linked to ancient rituals from the Bronze Age due to its copper alloys.
As Ray scrutinizes the orb's psychokinetic properties, it suddenly detonates, releasing extensive psionic energy across the city, which eventually disrupts the Ghostbuster firehouse's containment unit for the captured spirits. Up in the attic, Trevor Spengler finds candy wrappers, unknowing that a Slimer-like ghost is lurking nearby. Seeking further insight, Ray visits a New York librarian, Dr. Hubert Wartzki, who recounts the orb's history, detailing its origins over 4,000 years ago in Southwest Asia by a group known as the “Firemasters.” Their objective was to imprison a phantom god named Garraka, who sought global domination with his undead minions, using "Kusharit Umoti (The Death Chill)" as a means to instill fear. It turns out Nadeem is a descendant of the Firemasters, linked to the orb's creation and the ghost-catching legacy.
Unexpectedly, a lion statue outside the library gains a supernatural presence, prompting Phoebe to attempt stopping it but ending up causing further destruction, resulting in her arrest. The team scrambles to prevent the ghost from stealing the recording while Walter Peck seeks to use Phoebe's circumstances to banish the Ghostbusters irreversibly. After a heated argument with her mother, Callie, and Gary, Phoebe storms to her room. However, she soon dashes off with Melody to conduct a ghost projection experiment using Winston's extraction equipment. This risky endeavor allows her to experience ghosthood temporarily and engage with Melody, who reveals her allegiance to Garraka, eager for a passage to the afterlife in exchange for assistance.
Garraka takes control of Phoebe’s body to recite a mythical chant, reclaiming his powers and plunging the city into a blanket of chilling snow and ice. The Ghostbusters rally together, realizing the impending threat to their headquarters as Nadeem dons his grandmother’s Firemaster Brass Armor and embraces his newfound abilities just as Garraka approaches. However, the demon proves overwhelming, freezing their ranks one by one. With clever tactics, Phoebe harnesses brass to electrify Ego Spengler's proton pack, convincing Melody to switch sides, assisting Nadeem in embracing his Firemaster legacy.
With the help of Ray, Janine Melnitz, and the rest of the crew, they transform the containment unit into a grand ghost trap, using fire to obliterate Garraka, leaving nothing but ashes. Melody and Phoebe share a heartfelt farewell before Melody departs to reunite with her family in the afterlife. In the aftermath, despite their heroic efforts to rescue the city, Walter Peck remains ungrateful, yet the crowd forces him to reconsider his stance and reinstate Phoebe into the Ghostbusters. The adventure concludes as Slimer and other spooks break free, leading everyone, including Trevor, to chase after them in the iconic Ghostbuster vehicle.
As the credits roll, a passing truck driver is seen bringing Stay-Puft marshmallows to buy a snack from a vending machine, only to have mini-pufts swipe his delivery truck.
