O'Brien switched to civil engineering under his family's guidance, but his heart was still set on becoming an actor.

He moved to New York City and was "discovered" by theatrical impresario Charles Frohman who signed O'Brien to a three-year contract and put him in The Builder of Bridges, which opened on Broadway at the Hudson Theatre on October 26, 1909,[1][2] after he had appeared on Broadway in The Rollicking Girl (1905).

O'Brien's other Broadway credits included The Country Cousin (1917), Her Husband's Wife (1917), The Angel in the House (1915), The Bargain (1915), A Celebrated Case (1915), The Money Makers (1914), A Woman Killed with Kindness / Granny Maumee (1914), Kitty Mackay (1914), Tainted Philanthropy (1912), The Case of Becky (1912), and The Million (1911).

[4][5] World Film Corp. chief executive Lewis J. Selznick made O'Brien a screen star, putting him in an adaptation of Wilkie Collins' The Moonstone.

For his contributions to the motion pictures industry, O'Brien received a star on the Hollywood Walk of Fame at 1620 Vine Street on February 8, 1960.