Satan's School for Girls is set within the grim walls of Fallbridge College for Girls. Hoping to learn the truth behind the "suicide" of her younger sister, Beth Hammersmith enrolls in Fallbridge under the assumed name of Karen Oxford. Our heroine soon learns that the school is in the clutches of a coven of witches called "The Five" and that she herself has the right satanic qualities to enable The Five to take over the world
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The film opens with a mysterious person chasing a student, Martha Sayers (Terry Lumley). The same day, the police and her sister Elizabeth (Pamela Franklin) find her hanged in her room. The police rule her death as an unmotivated suicide, but Elizabeth refuses to believe this and investigates further. She decides to visit the exclusive academy that Martha attended, The Salem Academy for Women, despite warnings from Marthas roommate, Lucy Dembrow (Gwynne Gilford). Under the assumed name of Elizabeth Morgan, she enrolls at the college, where she is welcomed by her classmates Roberta Lockhart (Kate Jackson), Debbie Jones (Jamie Smith Jackson) and Jody Keller (Cheryl Ladd).
Elizabeth notes several strange occurrences, but postpones further investigation. Debbie has an outburst in class. The feared headmistress, Mrs. Jessica Williams (Jo Van Fleet), is worried about the influence of "the new girl". When Lucy commits suicide, Elizabeth resumes her investigation. She becomes intrigued with a painting of Martha in a dungeon-like room. Debbie, who painted it, is terrified of the painting and claims she invented the background, but Elizabeth finds an identical setting in a cellar on campus. When she is accosted by a man with a sharp weapon, Elizabeth flees.
The next night, Elizabeth returns to the cellar with Roberta, who is now suspicious as well. They locate a hidden room in which they find the dead body of Debbie, who earlier that evening had tried to leave the campus. Elizabeth suspects that Professor Delacroix (Lloyd Bochner) is responsible, considering his odd and mildly sadistic behavior. Elizabeth bursts into his office, finding him in a deranged state with a gun in his hand. He fears something supernatural is stalking him, and he jumps through the window. After running for some time, he ends up mired in a swamp, where he is beaten with sticks by several students including Jody.
Meanwhile, the otherwise popular Dr. Joseph Clampett (Roy Thinnes) reveals to Williams that he is responsible for all the murders. He orders the headmistress to evacuate the school. Elizabeth and Roberta are unaware of the evacuation. They discover the body of Delacroix, who has been brutally murdered. Elizabeth and Roberta turn to Williams for help, but she has gone insane.
When they are unsuccessful in calling the police, Elizabeth and Roberta go to the cellar to find a gun. Instead, they find Clampett leading a satanic cult. His followers (including Jody) believe that he is Satan incarnate, and Roberta reveals herself as his loyal servant. Elizabeth is able to escape when Clampett sets the school on fire, and she takes Williams with her. However, the other girls stay behind to sacrifice themselves to their leader. Clampett, who is actually supernatural, survives the fire and is seen outdoors, where he mysteriously vanishes.