Safran graduated from NYU Tisch with a Bachelor of Fine Arts in playwriting.
Safran was an executive producer and writer on the CW television series Gossip Girl and was the executive producer and showrunner for the second season of the NBC television series Smash. He shared writing credits with director Shana Feste for the screenplay of the 2014 remake of the 1981 film Endless Love.
In 2014, Safran was announced as the creator, executive producer and lead showrunner of the ABC thriller series Quantico. The first season premiered on September 27, 2015 and ended its run on May 15, 2016. The second season premiered on September 25, 2016 and ended its run on May 15, 2017.
On May 15, 2017, ABC renewed Quantico for a third season. The season which consisted of 13 episodes premiered on April 26, 2018 and ended on August 3, 2018. As part of the renewal process, it was revealed that Safran had to exit from his role as the primary showrunner. He is credited as a consultant and executive producer in the third season of Quantico.