On October 31, 1978, Michael Myers is shot and falls off a balcony. Taking shelter to recover from his injuries, Michael steals a kitchen knife from the home of an elderly couple, and kills a teenage girl living next door. Laurie Strode, who narrowly avoided being killed by Michael earlier in the night, is taken to Haddonfield Memorial Hospital, while Michael's psychiatrist, Dr. Sam Loomis, continues his pursuit of his patient. Accompanied by Sheriff Leigh Brackett, Loomis mistakes teenager Ben Tramer for Michael, when Ben gets hit by a squad car which pins him to another vehicle that bursts into flames, leading to his death. Upon learning his daughter Annie was killed by Michael, Sheriff Brackett goes off duty to inform his wife, leaving Deputy Gary Hunt in charge to help Loomis.
At the hospital, paramedic Jimmy becomes attracted to Laurie. Michael discovers Laurie's location after overhearing a news broadcast and makes his way to the hospital. Upon arrival, he cuts the phone lines and disables the cars. He wanders the halls in search of Laurie, killing security guards, doctors, and nurses that get in his way. Jimmy and nurse Jill Franco search the hospital for Laurie, who is trying to evade Michael. Jimmy finds the corpse of head nurse Virginia Alves and slips in a pool of blood on the floor, losing consciousness. While Laurie wanders the hospital, she has a few dreams in which she recalls of learning that she was adopted and of her being with a pre-teen Michael.
Meanwhile, Loomis is informed that Michael had broke into the local elementary school. As he investigates, he discovers clues connecting Michael to Samhain and the occult which might explain his seeming indestructibility, but his colleague, Marion Chambers, arrives to escort him back to Smith's Grove on the governor's orders under the enforcement of a US Marshal. En route, Marion tells Loomis that Laurie is Michael's sister; Laurie was put up for adoption after the death of Michael's parents, with the records sealed to protect the family. With the realization that Michael is after Laurie and being told that she was taken to Haddonfield Memorial, Loomis forces the Marshal to drive back to Haddonfield.
After killing Jill, a scalpel-wielding Michael finds and pursues Laurie through the hospital. She flees to the parking lot, and hides in Jimmy's car. Regaining consciousness, Jimmy exits the hospital and gets in the car to seek help, but he passes out on the steering wheel horn because of his injuries, alerting Michael to their location. Loomis, Marion, and the Marshal reach the hospital just in time to save Laurie. As Marion attempts to contact the police, Michael kills the Marshal and chases Loomis and Laurie into an operating theater. Michael stabs Loomis in the stomach, wounding him, but Laurie shoots Michael in the eyes, blinding him. Loomis and Laurie fill the room with ether and oxygen gas. Loomis orders Laurie to run and proceeds to cause an explosion, blowing up the operating room with him and Michael inside, immolating them both in the fire. Michael, engulfed in flames, stumbles out of the room before finally falling dead. The traumatized Laurie is transferred to another hospital.
- Donald Pleasence as Dr. Sam Loomis
- Jamie Lee Curtis as Laurie Strode
- Nancy Loomis as Annie Brackett
- Charles Cyphers as Sheriff Lee Brackett
- Dick Warlock as Michael Myers ("the Shape")