Lindsay and Jenny, two tourists from New York City, find themselves in a precarious situation while traveling through Germany. After getting a flat tire on their way to a nightclub, they seek assistance at the home of the seemingly benevolent Dr. Josef Heiter, portrayed by Dieter Laser. However, unbeknownst to them, Heiter has ulterior motives; he drugs the women with Rohypnol in their water and confines them to a makeshift medical ward in his home.
Dr. Heiter, a misanthropic and psychopathic surgeon, has a notorious background as a retired world-renowned expert known for separating conjoined twins. Though his previous experiments have proven disastrous, particularly his failed attempt to connect three Rottweilers into a single entity dubbed the "3Dog," Heiter aspires to take his twisted practice further. He envisions creating a new kind of creature by surgically linking the mouths of three victims to a single digestive system.
As fate would have it, Lindsay and Jenny soon find themselves shackled on gurneys beside a Dutch truck driver, who was among Heiter's earlier victims. Tragically, Heiter deems the trucker incompatible and mercilessly ends his life. The horror escalates when Heiter captures a Japanese tourist named Katsuro, played by Akihiro Kitamura. After a failed escape attempt by Lindsay, Heiter decides to make her the middle segment in his horrific creation—what he whimsically refers to as his "centipede."
In a graphic and gruesome surgical procedure, Heiter mutilates the mouths of Katsuro, Lindsay, and Jenny, connecting them in a horrifying sequence: Katsuro at the front, Lindsay in the middle, and Jenny at the back, thus forcing them into a shared existence that emphasizes their suffering. They face an awful reality as Heiter severs their knee ligaments, leaving them unable to stand, reduced to crawling in their new form.
Post-surgery, Heiter maliciously takes his creation into his living room, snapping grotesque photographs of each segment to further humiliate them. He keeps the centipede caged in a dog kennel, treating them as mere pets, subjecting Katsuro to degrading treatment, including forcing him to eat dog food while berating him with racist insults.
The situation grows increasingly dire as the centipede struggles with basic bodily functions. Katsuro, burdened with the pain of his circumstances, apologizes to the girls before he must defecate, leading to Lindsay being forced to ingest his excrement. As tensions rise, Heiter's patience wears thin when his sleep is disturbed by the centipede's struggles. He threatens to remove Katsuro's vocal cords, perpetuating a vile atmosphere of control and fear.
Meanwhile, two detectives, Andreas Leupold as Detective Kranz and Peter Blankenstein as Detective Voller, arrive to investigate the apparent disappearances of the tourists and the truck driver. Sensing something amiss, they start probing deeper into Heiter’s home, leading Heiter to consider adding the detectives into his grotesque experiment. However, once they become suspicious and seek a search warrant, the victims seize an opportunity to escape, culminating in a violent confrontation between Katsuro and Heiter.
In a moment of desperation, Katsuro confronts Heiter about his treatment of others and ultimately takes his own life by slitting his throat. The detectives, unaware of the lurking danger, resume their search. Heiter, nursing his injuries following the attack, resorts to defending himself brutally. When Detective Voller succumbs to the effects of the earlier drugging, Heiter takes advantage of the situation, killing him and then fatally wounding Detective Kranz.
Back in a chilling atmosphere of despair, Lindsay and Jenny hold onto each other as life wanes from Jenny due to her infection. As she passes away, Lindsay is left utterly alone in the house, distraught and trapped between the bodies of her deceased companions, a haunting end to a tale filled with unspeakable horror.