He began on Broadway at the Lyceum Theatre as assistant director of revivals of You Can't Take It with You (1965–67) and The Cherry Orchard (1968), and in a number of other shows, also sometimes contributing additional lyrics to songs.

In the meantime, he directed dozens of Shakespeare plays and other works at the Old Globe, the Lowell Davies Festival Theatre, off-Broadway and elsewhere.

After becoming Artistic Director of the Old Globe Theatre in 1981, O'Brien continued directing productions there, including a revival of Thornton Wilder's The Skin of Our Teeth, which was televised live to open the 1983 season of PBS's "American Playhouse" series, and the world premieres of Stephen Metcalfe's Emily (1986) and A. R. Gurney's The Cocktail Hour (1988).

[7] On Broadway, he next produced two more Old Globe productions, Imaginary Friends (2002–03), which he directed, and the one-performance flop, Oldest Living Confederate Widow Tells All (2003), which he did not.

O'Brien next directed Tom Stoppard's trilogy of plays The Coast of Utopia (2006–07) at Lincoln Center in New York City, winning both the Tony and Drama Desk Awards.

On television, O'Brien has directed six movies for "American Playhouse", including An Enemy of the People, I Never Sang for my Father, All My Sons, and Painting Churches.

[2] O'Brien's latest directoral efforts at the Old Globe include Shakespeare's Twelfth Night, Chekhov's The Seagull, in a new version by Stoppard, and Brendan Behan's The Hostage.

I have had the enviable opportunity to direct everything from Shakespeare to new American works to Broadway-bound musicals, all under the supportive and watchful eye of an enthusiastic San Diego community.'

[13] In 2009, he directed the premiere of the Michael Jacobs play Impressionism at the Schoenfeld Theatre, starring Jeremy Irons and Joan Allen.

[18] In Fall 2024, O'Brien is set to direct The Roommate by Jen Silverman on Broadway, starring Patti Lupone and Mia Farrow at the Booth Theatre.