He is best known today as the lead actor in F. W. Murnau's 1927 film Sunrise: A Song of Two Humans and subsequent appearances in a number of Westerns in the 1930s and 1940s.

In 1917, O'Brien enlisted in the United States Navy to fight in World War I, serving on a submarine chaser.

One of his early roles was in the 1922 George Melford-directed drama Moran of the Lady Letty, most notable for starring Rudolph Valentino.

[2] O'Brien spent the remainder of the 1920s as an extremely popular leading man in films, often starring in action and adventure roles with popular actresses of the era, such as Alma Rubens, Anita Stewart, Dolores Costello, Madge Bellamy, Olive Borden (with whom he was linked romantically during the 1920s), and Janet Gaynor.

With the advent of sound, O'Brien displayed a strong, confident voice and remained a leading star of westerns and outdoor adventures.

In 1938, he signed with RKO Radio Pictures to headline a western series; O'Brien (often atop his horse Mike) was well received and was ranked consistently among the top 10 cowboy stars.

Following his service in World War II, O'Brien occasionally took featured parts in films directed by John Ford, including Fort Apache, She Wore a Yellow Ribbon, and Cheyenne Autumn.

For some reason (some say his family did not approve of Olive), they ended their relationship and he eventually married actress Marguerite Churchill on July 15, 1933.