While working as a high school English teacher, he wrote the book The 25th Hour, and later adapted it into a screenplay, which was filmed starring Edward Norton and 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 was published. He has been working on an adapted screenplay of the Charles R. Cross biography of Kurt Cobain but as of 2010 the screenplay has not been used. He is also working with D.B. Weiss as executive producer, showrunner and writer on Game of Thrones, HBO's adaptation of the A Song of Ice and Fire novel series by George R.R. Martin.
On April 10, 2014, Benioff announced he and D.B. Weiss had taken on their first feature film project to write, produce and direct Dirty White Boys, a novel by Pulitzer prize-winning author Stephen Hunter.