While working as a high school English teacher, he wrote the book called The 25th Hour and received positive recognition for the book. He later adapted the book into a screenplay, which was filmed starring Edward Norton and was directed by Spike Lee. He then wrote a collection of short stories titled When the Nines Roll Over (And Other Stories) in 2004.

Benioff drafted a screenplay of the mythological epic Troy (2004) for which Warner Bros pictures paid him $2.5 million. He also wrote the script for the psychological thriller Stay (2005), which was directed by Marc Forster and starred Ewan McGregor and Naomi Watts. His screenplay for The Kite Runner (2007), adapted from the novel of the same name, marked his second collaboration with director Marc Forster. He was hired in 2004 to write the screenplay for the X-Men spin-off X-Men Origins: Wolverine (2009), and worked on the script for three years.

In 2008, his second novel, City of Thieves, A Novel was released. He is currently working on an adapted screenplay of the Charles R. Cross biography of Kurt Cobain. It is unknown if the screenplay has been developed. He is also working with D.B. Weiss as executive producer, showrunner and writer on Game of Thrones, HBO's adaptation of George R.R. Martin's A Song of Ice and Fire series of novels.