In her desperate quest for relief, Karen Tandy, portrayed by Susan Strasberg, finds herself confronted by an unusual malady—a persistent tumor growing on her neck. This harrowing journey leads her to a prestigious hospital in San Francisco, where she meets Dr. Jack Hughes, played by Jon Cedar. In a shocking revelation, Dr. Hughes uncovers that the tumor is not what it seems; rather, it is a developing fetus. As Karen consents to undergo surgery to remove this anomaly, she seeks comfort from old friends, including Harry Erskine, a dubious fortune teller brought to life by Tony Curtis.
Under Harry’s roof, Karen begins to whisper an ominous phrase in the night: "pana witchy salatoo," a harbinger of the chaos that is yet to come. When the surgery goes terribly wrong, leaving the surgeon shaken and injured, the series of events spirals out of control. As if that weren't enough, one of Harry's clientele experiences an alarming seizure, levitating before crashing down the staircase. Alarmed that Karen is besieged by dark influences, Harry turns to former psychic Amelia Caruso, played by Stella Stevens, and her associate MacArthur for guidance. They soon join forces with Mrs. Karmann, embodied by Ann Sothern, Amelia's aunt who claims to wield ancient wisdom.
During a turbulent thunderstorm, this eclectic group attempts to summon the dark spirit haunting Karen through a séance. However, their efforts are thwarted by the violent weather and mysterious warnings about the entity resembling a wooden Native American statue. They seek counsel from Dr. Snow, an aging anthropologist portrayed by Burgess Meredith, who narrates tales of 400-year-old Indian medicine men known for their supernatural abilities.
Their pursuit of answers leads them to the enigmatic John Singing Rock, characterized by Michael Ansara, a reclusive medicine man. Initial hostility soon gives way to insight as John attributes Karen's predicament to the existence of manitou—spirits that permeate their environment. However, his assistance comes at a steep cost of $100,000, alongside tobacco, which poses a significant challenge for Harry as he navigates this dangerous realm of ancient mysticism and modern desperation.
Upon arriving at the hospital, Harry and John swiftly lay a circle of fine sand around Karen’s bed—a symbolic barrier intended to confine the spirit’s power and prevent any further chaos. The dark entity reveals itself through Karen as Misquamacus, an avenging Native American shaman angry over the colonial devastation of his lands and people. In a calculated move, Misquamacus warns John to stay out of Harry and Karen's conflict, establishing himself as a formidable adversary.
As John prepares to challenge Misquamacus's potent energy, he calls upon the strength of other manitou, but their silence is deafening. Undeterred, he resolves to stop the vengeful spirit, which demonstrates its power by animating a deceased nurse and causing mayhem. Escalating tensions lead to Misquamacus unleashing the terrifying Lizard of the Tree, a demon that shatters their defenses and attacks Dr. Hughes.
In the aftermath, Harry discovers the hospital floor transformed into a frozen wasteland—a grim testament to the spirit's wrath. When he finds John, he sees the evidence of Misquamacus's brutal assaults, as John's face bears gruesome wounds. Their conversation is abruptly interrupted as the shaman appears during a conjured snowstorm, prompting Harry to seize the moment and retaliate by hurling a typewriter, momentarily weakening the supernatural threat.
Recognizing an opportunity, Harry devises a plan to leverage the nearby electrical equipment as manitou to counteract their nemesis. John's hesitant agreement leads to a collaborative effort, but a violent earthquake signifies the impending arrival of the Great Old One, a demon summoned through the portal that Misquamacus had opened.
With renewed determination, Harry instructs Dr. Hughes to activate the hospital machinery, hoping to bridge the mystical energies with their technology. Together, Harry and John confront the looming threat of Misquamacus, plunging into an unknown realm where Karen's consciousness is ensnared in a surreal struggle against powerful phantom forces. Despite John's valiant attempts to harness the machine manitou, failure only drives Harry to unleash his cunning in a desperate bid to rejuvenate Karen’s spirit.
As she gradually awakens, a transformation begins. Tapping into the mystical energies coursing through the manitou, Karen ultimately triumphs over Misquamacus and the dark forces that lurk beyond. Once the chaos subsides, a poignant reunion between Harry and Karen unfolds, signifying their shared struggles and victories. With John by their side, Harry bids farewell to his ally as he heads to the airport. John's cautious reminder that this battle may not be the last looms over their parting, alerting them to the fact that while Misquamacus's physical form may have been defeated, its lingering essence remains a constant threat to their world.
