Originally a musician and Songwriter, Katz fronted a rhythm and blues group called "Katz and Jammers" before serving as the musical Director for Robin Williams' 1979 standup tour. In 1998, he released Brandon Project, a blues album.

Dr. Katz originally aired on Comedy Central from 1995-2002, and starred Katz as a professional therapist whose patients were chiefly other comedians and actors. He received a Primetime Emmy Award for his work on the show in 1995 for Outstanding Voice-Over Performance. His voice can also be heard in the animated series Home Movies, a show with many ties to Dr. Katz, as well as on the Adult Swim animated comedy series Squidbillies where he performed uncredited voice-overs as "The Rapist" in Season 2 and as the Holodeck Therapist in Season 5.

In 1996, Katz was diagnosed with multiple sclerosis. The initial symptoms began in 1996: "I was working on a TV show called Ink with Ted Danson, and after every episode we would take a curtain call and I noticed that I needed a head-start."

In 2007, Katz joked to Blast Magazine entertainment Editor Bessie King about the success of his Comedy Central show and the recent release of the full series on DVD. "I’m so proud of that work and I’m a compulsive name dropper, [but] when I did a movie with Ice Cube over the summer I said...I hope my best work is not behind me but if it is, I’m glad it's Dr. Katz," he said. In 2007, he released a stand-up album titled Caffeinated. In 2009, he can be seen (or heard) as Freezy, the Burl Ives-inspired animated snowman star of Turbocharge: The Unauthorized Story of the Cars, a comedy biopic about The Cars, which Katz narrates throughout.

In 2011, he starred as Jon Gold on the web series Explosion Bus created by Tom Snyder and co-developed with Katz, Snyder and Tom Leopold. In the spring of 2012, Katz taught a theater class at Brandeis University in Short Form Comedy. On September 3, 2014, Katz appeared on Ken Reid's TV Guidance Counselor Podcast.