Benioff was born David Friedman in New York City, to a Jewish family with roots in Romania, Austria, Poland and Russia. He is the son of Barbara (Benioff) and Stephen Friedman, who is a former head of Goldman Sachs. He is a distant cousin of Marc Benioff. As an adult, he uses the last name of Benioff, his mother's maiden name, to avoid confusion with other Writers named David Friedman. He is the youngest of three children (Suzy, Caroline, and David). He grew up in Manhattan, first in Peter Cooper Village, then on 86th Street where he spent most of his childhood, before eventually moving near the U.N. headquarters when he was sixteen.

He is an alumnus of The Collegiate School and of Dartmouth College. While at Dartmouth he was a member of Phi Delta Alpha Fraternity and the Sphinx Senior Society. After he graduated in 1992, he worked in a number of jobs; for a time as a club bouncer in San Francisco, and he became a high school English Teacher at Poly Prep in Brooklyn, New York City for two years, and served as the school's wrestling coach. Benioff became interested in pursuing an academic career, and went to Trinity College Dublin in 1995 for a one-year program to study Irish literature, and while in Dublin he met D.B. Weiss, who would later become his collaborator. He wrote a thesis on Samuel Beckett while at Trinity College, but decided against a career in academia after writing the thesis. He worked as a radio DJ in Moose, Wyoming for a year - mostly as a side job, which he mainly accepted to take a year in the countryside as a writer's retreat. He then applied to join the Creative Writing Program at the University of California Irvine after reading The Mysteries of Pittsburgh by Michael Chabon (an alumnus there), and received a Master of Fine Arts degree in creative writing there in 1999.

In 2001, People magazine included Benioff on its list of America's Top 50 Most Eligible Bachelors.

He was hired in 2004 to write the screenplay for the X-Men spin-off X-Men Origins: Wolverine (2009). In preparing to write the script, he reread Barry Windsor-Smith's "Weapon X" story, as well as Chris Claremont and Frank Miller's 1982 limited series on the character (his favorite storyline). Also serving as inspiration was the 2001 limited series Origin, which reveals Wolverine's life before Weapon X. Hugh Jackman collaborated on the script, which he wanted to be more of a character piece compared with the previous X-Men films. Skip Woods was later hired by Fox to revise and rewrite Benioff's script. Benioff had aimed for a "darker and a bit more brutal" story, writing it with an R rating in mind, although he acknowledged the film's final tone would rest with the producers and Director.

On September 30, 2006, Benioff married Actress Amanda Peet in New York City. Together they have three children: Frances "Frankie" Pen Friedman, born February 20, 2007; Molly June Friedman, born in 2010; and Henry Peet Friedman, born December 6, 2014. The family lives in Manhattan and Beverly Hills, California.

In 2008, his second novel, City of Thieves was published. He has been hired by Universal Pictures in October 2007 to write an adapted screenplay of the Charles R. Cross biography of Kurt Cobain but the screenplay was not used.

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. On July 19, 2017, Benioff announced that he and Weiss are going to begin production on another HBO series, titled Confederate, after the final season of Game of Thrones. Benioff and Weiss said, "We have discussed Confederate for years, originally as a concept for a feature film, but our experience on Thrones has convinced us that no one provides a bigger, better storytelling canvas than HBO."

On February 6, 2018, Disney announced that both Benioff and Weiss will write and produce a new series of Star Wars films after the finale season of Game of Thrones is completed in 2019.