In a small, undisclosed city, a new drug known as "Soy Sauce" is circulating, promising out-of-body experiences and inhuman knowledge to its users. However, those who return from their trips are not always human, and an otherworldly invasion is underway. A slacker named David Wong and his friend John are caught in the middle, trying to uncover the truth behind the drug and the mysterious occurrences happening around them. As they delve deeper into the mystery, they encounter a strange creature, a ghostly door, and a celeb psychic who claims to have the answers. But, things take a turn for the worse when they discover that the source of the strange happenings is Korrok, an eldritch biological supercomputer who wants to conquer new dimensions. With the help of Bark Lee, a dog who has been infected by the Soy Sauce, David and John must find a way to stop Korrok before it's too late. The fate of humanity rests in their hands.

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Some movies that have similar genres and were produced around the same time as John Dies at the End include The Voices, Therapy for a Vampire, Pride and Prejudice and Zombies, What We Do in the Shadows, Tucker and Dale vs. Evil, Anna and the Apocalypse.