Possessing a distinctive deep voice, he has appeared in numerous television and film roles in both live-action and animation mediums.

Garrett was initially successful as a stand-up comedian in the early 1980s. Taking advantage of that success in the late 1980s, Garrett began appearing in television and film, in minor and guest roles. His first major role was Robert Barone on the CBS sitcom Everybody Loves Raymond. The series debuted September 13, 1996, and ran for nine seasons. In 2002, he gave an Emmy-nominated and critically lauded performance as Jackie Gleason in the television film Gleason.

Garrett's film roles include Casper (1995), A Bug's Life (1998), An Extremely Goofy Movie (2000), Stuart Little 2 (2002), Finding Nemo (2003), Garfield (2004), The Pacifier (2005), Ratatouille (2007), Tangled (2010), Hoodwinked Too! Hood vs. Evil (2011), The Incredible Burt Wonderstone (2013), Teenage Mutant Ninja Turtles: Out of the Shadows (2016), and Christopher Robin (2018). Garrett also played the leading role of Eddie Stark on the Fox sitcom 'Til Death from 2006 to 2010. From 2006 to 2014, he played the Easter Island Head in the Night at the Museum trilogy. From 2018 to 2020, he starred in the ABC sitcom Single Parents. In 2021, Garrett also helped create Disney+'s Big Shot with David E. Kelley and Dean Lorey. He is also known for voicing the Big Dog on 2 Stupid Dogs.

Garrett has won three Primetime Emmy Awards, with three other nominations. He is still prominent within stand-up comedy and owns a comedy club at the MGM Grand in Las Vegas, called Brad Garrett's Comedy Club, where he performs regularly.