In 1950 Holmes made his first but uncredited movie appearance at 6 weeks old as the infant Butch, one of the children John Wayne rescues in the submarine under his command in the war movie Operation Pacific. Holmes' grandfather, Soldier Graham, was the gaffer on that film. In 1954, Holmes made his television debut as young Jimmy Evans on The Jack Benny Program, a role that he repeated seven years later in 1961. His next television appearances were in 1957 on Wire Service, The Walter Winchell File, and General Electric Theater, the latter as Tiny Tim in the episode "The Road to Christmas," with the host Ronald W. Reagan.

Subsequent television appearances followed on Leave It to Beaver, Father Knows Best, and as the youthful Vint Bonner title character on John Payne's NBC western, The Restless Gun, in the second-season premiere in 1958.

On October 20, 1959, Holmes appeared as Davey Morris in the episode "Night of the Kill" of the anthology series, Alcoa Theatre In 1960, he guest starred on Bonanza, Bachelor Father, The Andy Griffith Show, and on ABC's 77 Sunset Strip in the episode "The Valley Caper."

In 1961, prior to joining Laramie, Holmes appeared as Charlie Baker on Frank Aletter's CBS situation comedy Bringing Up Buddy and on Annie Fargé's Angel on the same network. He also guest starred on ABC's The Adventures of Ozzie and Harriet.

Holmes's last television appearances were in 1964 as Tim Anders in the second-season episode "Another's Footsteps" of NBC's The Virginian and as Danny Blake in "Those Who Stay Behind" on ABC's Wagon Train. He had also appeared in two previous Wagon Train episodes in 1958 and 1961.