In 1973, he moved to San Francisco, California and soon became involved in the Bay Area jazz scene of that time, playing bass for established artists Charles Lloyd, Joe Henderson, Dexter Gordon, Joe Pass, Woody Shaw, Eddie Henderson, and Bobby Hutcherson.

While on tour in Los Angeles in 1976, O'Hearn met musician Frank Zappa, who offered him a job as bass player in his band—a position he held for over two years.

O'Hearn's solo career was spurred in large part by former Tangerine Dream member Peter Baumann, who had been conceiving of a new music label that would showcase progressive instrumental music—a niche earlier explored by Group 87.

Baumann formed the Private Music label in late 1984, and produced O'Hearn's debut solo album, Ancient Dreams (1985).

O'Hearn followed Ancient Dreams with two more albums—Between Two Worlds (1987), which earned the artist his first Grammy nomination, and Rivers Gonna Rise (1988).

O'Hearn also co-produced several tracks for guitarist Colin Chin's Intruding on a Silence, featuring Mark Isham on trumpet.

O'Hearn released his fourth solo album Eldorado in 1989, which blended elements of World Music with warm keyboard textures.

In 1992, O'Hearn composed and performed the music score for White Sands, a crime thriller starring Willem Dafoe and Samuel L. Jackson.

Later that year he composed the score to Silent Tongue, written and directed by Sam Shepard and starring Alan Bates, Richard Harris, River Phoenix and Dermot Mulroney.

Featuring contributions from David Torn and former bandmates Terry Bozzio and Warren Cuccurullo, Trust earned O'Hearn his second Grammy nomination.

O'Hearn continued to tour with Hiatt through 2010 and recorded on his following releases: The Open Road (2010), Dirty Jeans and Mudslide Hymns (2011), and Mystic Pinball (2012).

In December 2013, a various artists album titled Nashville Indie Spotlight was released, which includes a new piece by Patrick O'Hearn and Peter Maunu called "Out of Reach".

In August 2024, O'Hearn released an EP titled Quattro Amici, which is four tracks from his first album Ancient Dreams that have been reworked in varying degrees.