O'Brien has won three Tony Awards and been nominated for seven more, and won five Drama Desk Awards. He has directed and produced musicals, including The Full Monty and Hairspray, contemporary dramas such as The Piano Lesson, Shakespeare, including Hamlet and Henry IV, and opera, including Il trittico at the Metropolitan Opera''.
He has also been associated with some notorious Broadway failures. In 1972, he wrote the lyrics and co-wrote the book for the The Selling of the President, which closed after five performances. He also co-produced the stage adaptation of Oldest Living Confederate Widow Tells All, which closed after only one performance.
As Artistic Director of the Old Globe, O'Brien co-produced Stephen Sondheim's Into the Woods (1987–89), Rumors (1988–90) and the drama The Piano Lesson (1990–91), for which he won his first Drama Desk Award. Returning to directing, O'Brien helmed Two Shakespearean Actors (1992). He co-produced Two Trains Running (1992) and Redwood Curtain (1993). He also directed and produced a revival of Damn Yankees (1994–95), Hapgood (1995, winning the Lucille Lortel Award for Direction), a flop called Getting Away With Murder (1996) and produced Play On! (1997). He next directed a revival of The Little Foxes (1997), a new comedy, More to Love (1998), which closed in three days, and produced Getting and Spending (1998). O'Brien also has occasionally directed for television over the years.
O'Brien had a hit with The Full Monty, which he directed and produced (2000-2002), and critical success with the drama The Invention of Love (2001) for which he won the Drama Desk Award for direction. An even bigger hit was Hairspray, which premiered in 2002 and is still running. This marked his first Tony Award win, and he also received another Drama Desk Award. In 2002, he was honored with the prestigious "Mr. Abbott" Award from the Stage Directors and Choreographers Foundation. 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. He returned to Shakespears, directing Henry IV (2003–04), for which he won both the Tony and the Drama Desk Awards, and progressed from the sublime to the ridiculous, directing and producing Dirty Rotten Scoundrels (2005–06). He then produced other works including the Old Globe's annual musical adaptation of Dr. Seuss' How the Grinch Stole Christmas! (Chrismas 2006–07 and 2007–08).
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 for "Part 1 - Voyage". He then he directed Giacomo Puccini's trilogy of operas Il trittico for the Metropolitan Opera. Other opera productions have included Peter Maxwell Davies' The Lighthouse for San Diego Opera, Mozart's The Magic Flute for the San Francisco Opera, Verdi's Aida for Houston Grand Opera, Kurt Weill's Street Scene for New York City Opera, which was televised on "Live from Lincoln Center", and Puccini's Tosca for Santa Fe Opera. 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. His Broadway revival of Most Happy Fella and staging of The Good Doctor were produced for PBS.
O'Brien's recent 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. In stepping down as Artistic Director of the Old Globe Theatre at the end of 2007, O'Brien said, "“I consider myself truly blessed to have been able to enjoy such a full and varied career at the Globe. 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."
He is also listed as director of Andrew Lloyd Webber's sequel to The Phantom of the Opera scheduled for 2009.