In CBS's Threshold Benedict played physicist Lucas Pegg, member of a secret government team investigating the first contact with an extraterrestrial species.

In seasons 4, 5, 10, 11, 14 and 15 of Supernatural he played a writer, Chuck Shurley, previously thought to be a prophet of the lord but later revealed to be God, who eventually becomes the series main antagonist.

Additional early television series credits include Birds of Prey and Come to Papa, with guest appearances on NCIS, CSI, Monk, Medium, Chicago Hope, NYPD Blue, Buffy the Vampire Slayer, Snoops, Burn Notice, and Beverly Hills, 90210.

Other Recurring characters include roles in Bosch, NCIS: New Orleans, Masters of Sex, Fox's Touch, Franklin & Bash, the digital series Susanna with Anna Paquin, and he was the irreverent power agent Jeremy Berger in the Starz Original comedy series Head Case.

In 2005 he starred as Calvin in the cult comedy Waiting... with Ryan Reynolds, and later revised the role in the sequel Still Waiting... Other films include Kicking & Screaming, with Will Ferrell, Group Sex, Say Goodnight with Aaron Paul, Two Days, with Paul Rudd, The First $20 Million Is Always the Hardest, starring Rosario Dawson, and Not Another Teen Movie.

In 2018, he had a starring role in the horror film 30 Miles from Nowhere, with Carrie Preston, Clearmind, and Connescence with Kevin Bacon.