Brendan O'Brien was born in Hollywood, California, as the son of actors Edmond O'Brien and Olga San Juan. He first got his start as an actor with a supporting role in the TV movie Honor Thy Father (1973), then followed it up with subsequent appearances in films like 3 Küçük Ninja Eğleniyor (1998), P.U.N.K.S. (1998), and Race to Space (2001). O'Brien's biggest claim to fame, however, arrived when he was contacted by Naughty Dog co-founder Jason Rubin to provide voices for the company's then-upcoming video game Crash Bandicoot (1996) for the PlayStation, in which he provided the voices of the title character, Doctor Neo Cortex, and Doctor Nitrus Brio. Following the game's release, he would continue to voice Crash in subsequent installments up until the release of Crash Bandicoot: The Wrath of Cortex (2001), and would also provide voices for the HBO series Spicy City (1997) and Spawn (1997).

On March 23, 2023, O'Brien died at the age of 60. Among one of his last roles was an appearance on the TV show Riverdale (2017) in 2020, in which he played a math teacher. By the time he died, the role of Crash Bandicoot has since been passed on to numerous other voice actors, with Chip Chinery, Steve Blum, and Jess Harnell being among them.