In the early 1980s, Brion and musician/producer Bill Murphy began a writing collaboration in New Haven, Connecticut. They eventually enlisted Bassist Don "Riff" Fertman and together formed The Bats, (not to be confused with the New Zealand group of the same name). The Bats released a single, "Popgun" and one album How Pop Can You Get?, on Gustav records in 1982. The recordings had much critical acclaim, but little commercial success, and the trio eventually disbanded.

In 1987, Brion moved to Boston, where he played solo gigs, formed the short-lived band World's Fair and became a member of the last touring version of Aimee Mann's new wave band 'Til Tuesday. He contributed guitar work to Jellyfish's 1993 album Spilt Milk, and in 1994, joined Dan McCarroll, Buddy Judge and ex-Jellyfish Guitarist Jason Falkner in the short-lived pop band The Grays. He also played guitar on The Wallflowers' hit song "One Headlight." Brion played numerous instruments on Sam Phillips' 1996 release Omnipop. Brion is featured as keyboardist and Drummer on Marianne Faithfull's 2003 album, Kissin Time, and co-wrote a song, "City of Quartz", for her next work, 2005's Before the Poison.

After being recognized as an accomplished session player, Brion branched out into production on then-girlfriend Mann's 1993 solo debut, Whatever, and its follow-up, I'm With Stupid. He has also produced albums by Fiona Apple, Rufus Wainwright, Eleni Mandell, Rhett Miller, Robyn Hitchcock, Brad Mehldau and Evan Dando, and co-produced Kanye West's Late Registration in 2005.

Brion was signed to the Lava/Atlantic label in 1997, but was released from his contract after turning in his solo debut album Meaningless; the album was released independently in 2001.

He has earned Best Score Soundtrack Album Grammy nominations for his work on 1999's Magnolia and 2004's Eternal Sunshine of the Spotless Mind.

He dated comedic Actress Mary Lynn Rajskub for five years until they broke up in the fall of 2002.

In April 2006, recurring tendonitis in Brion's right hand forced him to cancel all of his upcoming Largo shows. As a temporary 'farewell', he played one show only using his left hand, even looping his songs as he normally does and playing the drums with one stick. He is now back to playing at Largo on a regular basis.

More recently, Brion has produced recordings by British pop performer Dido, Spoon, and Keane, as well as 2010's False Priest by Of Montreal. Brion also produced Best Coast's second album which was released in early 2012.

Recalling his approach to the Largo shows with Chicago Tribune music Editor Lou Carlozo, Brion said: "I taught my hands to follow whatever was coming into my head—and wherever my consciousness would go, I had to push my hands to follow. And at some level, you just had to abandon any concern about how you’d look. Performing without a set list: That was special."

In March 2016, Brion performed his score for Punch-Drunk Love with Wordless Music Orchestra in both Los Angeles and New York City, at the Ace Hotel and the Brooklyn Academy of Music, respectively. Norah Jones provided guest vocals in New York and Joanna Newsom in Los Angeles.

In February of 2018, Brion performed before John Mulaney during Mulaney’s special, Kid Gorgeous. Brion performed during Mulaney’s New York City leg of his tour, playing packed houses at Radio City Music Hall. Brion’s appearance surprised audiences, but his versions of classic rock songs on Radio City’s Mighty Wurlitzer pipe organ were welcome warmups for Mulaney.