As a child he was fascinated by films and the theatre and decided to make his career as an actor after his father took him to see Charlie Chaplin and Jackie Coogan in The Kid in 1921. After years in stage, film and television Whitehead struggled in the Hollywood Studio system, a pacifist in World War II and became dissatisfied with the roles he was given, and then first heard of the Bahá'í Faith in 1949. At his first informational meeting on the religion, Whitehead heard well-known researcher Marzieh Gail. Whitehead joined the religion late in 1950, gave public talks on the religion such as at World Religion Day observances and other occasions in the 1950s, went on pilgrimage to its spiritual and administrative center in Haifa in 1955. He also attended the first Bahá'í World Congress in 1963 in London. He then pioneered to Ireland while also taking to the Dublin theatrical opportunities. Whitehead was elected to the Local Spiritual Assembly of Dublin and the National Spiritual Assembly of Ireland on which he served for 15 years following its formation in 1972. From about 1973 through the end of his life Whitehead devoted much of his time to the concerns of the religion including work resulting in publishing three books collecting biographies of early Bahá'ís while in his 6th decade but he also supported the Irish Actors' Equity and the Screen Actors' Guild and served on the executive of the Irish branch of PEN, the international writers' club.

Whitehead first appeared on Broadway in Martin Beck Theatre performing in The Lake (1933) in 55 performances from December 1933 to February 1934 (which was Katharine Hepburn's first Broadway leading role) and 11 other plays by 1939. Hepburn encourages his early career.

The Scoundrel (1935) by Ben Hecht, and Charles MacArthur which won a 1936 Oscar for Best Original Story was Whitehead's first film. Whitehead most famously played Al Joad (Henry Fonda's younger brother) in John Steinbeck's Grapes of Wrath (1940) which was nominated for, and won, several Oscars. Whitehead starred as Clarence in a stage production of Life with Father with Lillian Gish among a total of more than 50 films and TV series episodes performances. Whitehead's first TV episode was The Arrow and the Bow in Cavalcade of America in 1953 and continued in other shows like Gunsmoke (1958), Bonanza (1960), and two episodes of Alfred Hitchcock Presents (1960–61). In 1961 he made a guest appearance on Perry Mason as murderer Harry Beacom in "The Case of the Cowardly Lion." Shortly thereafter Whitehead moved to Ireland and participated in theatre arts there.

O. Z. Whitehead was one of the last surviving members of John Ford's "stock company" of character actors. Along with John Carradine, Donald Meek, Ward Bond, Ben Johnson, Harry Carey, Jr. et al., Whitehead was one of the many actors regularly employed by Ford to breathe life into even the smallest roles in his films. His best-known part was that of Al in Ford's 1940 adaptation of John Steinbeck's novel The Grapes of Wrath.

Following his move to Ireland he established the "O. Z. Whitehead Award" supporting theatre in 1966, the first year including Dr. Michael McDonnell, for his play All Gods Die on Friday. Other winners have been Ivy Bannister, Aodhan Madden, and Francis Harvey.

Whitehead died of cancer in Dublin in 1998, at the age of 87.