Danielewski was born in New York City, the son of Polish avant-garde film director Tad Danielewski and the brother of singer/songwriter Annie Decatur Danielewski, a.k.a. Poe.

Danielewski studied English Literature at Yale. He then decided to move to Berkeley, California, where he took a summer program in Latin at the University of California, Berkeley. He also spent time in Paris, preoccupied mostly with writing.

In the early 1990s, he pursued graduate studies at the USC School of Cinema-Television. He later served as an assistant editor and worked on sound for Derrida, a documentary based on the life of the Algerian-born French literary critic and philosopher Jacques Derrida.

House of Leaves, Danielewski's first novel, has gained a considerable cult following and won numerous awards, including the New York Public Library's Young Lions Fiction Award. His second novel, Only Revolutions, was released in 2006. Though released to less critical acclaim than his debut, the novel was a finalist for the 2006 National Book Award.

In 2000, Danielewski toured with his sister across America at Borders Books and Music locations, promoting Poe’s album Haunted, which reflects elements of House of Leaves.

He is a fan of Biffy Clyro as the band discovered when Danielewski attended one of their shows after they borrowed the title of his novel Only Revolutions for their own album.

On Sept. 15, 2010, Danielewski's next novel was announced on his message boards: "Later this month publishers will receive the first 5 volumes of Mark Z. Danielewski's 27 volume project entitled The Familiar. The story concerns a 12 year old girl who finds a kitten..."