Highway Killers tells the story of two friends who rent a car and start killing people who cross their path. The two men, who set out on the road after renting a car, begin robbing shops and gas stations along the highway under the influence of heavy drugs. Meanwhile, the pair, who start killing people who cross their path with a pump-action shotgun, make plans to flee the country via the southern border.

Esra and Orhan live together in Istanbul. After her mother's death, Esra married her father and was raised by her paternal grandmother. When his grandmother passed away, he came to Istanbul and did not return to his village for many years. Esra returns to her village with Orhan with the news of her father's death.

Bayram and Gül live a modest life with their son Ali in a quiet village in Anatolia. Everything changes when strange, unexplained events begin to occur in their home. While Bayram and Gül seek help from religious scholars to unravel the mystery, Ali, a young man who uses science as a guide and acts logically, denies what is happening. However, the situation soon spirals out of control. The darkness in the house begins to directly target Ali. His psychology begins to crumble, and his perception of reality is shaken.