Lockwood's two series came early in his career, and each lasted only a single season. ABC's Hawaii-set Follow the Sun (1961–62) cast him in support of Brett Halsey and Barry Coe, who played adventurous magazine Writers based in Honolulu. Lockwood was Eric Jason, who did the legwork for their articles, but his on-screen time was limited since most of the plot focused on Halsey or Coe. In the story, Eric Jason was said to have been born on December 7, 1941 (Pearl Harbor Day), but Lockwood was actually born nearly five years earlier. Another series regular was Gigi Perreau, who played the writers' secretary. Lockwood had earlier played a soldier with a crush on Mary Stone (Shelley Fabares) on the ABC sitcom, The Donna Reed Show.

Between 1959 and 2004, Gary Lockwood gained roles in some forty theatrical features and made-for-TV movies and eighty TV guest appearances, including the CBS 1975 family drama Three for the Road and Barnaby Jones starring Buddy Ebsen, in which he appeared many times as a villain.

Lockwood was married to Actress Stefanie Powers in the 1960s and Denise DuBarry in the 1980s.

Lockwood made an impression in a supporting role in the film Splendor in the Grass (1961) and appeared in ABC's Bus Stop (also 1961) as a 24-year-old rodeo Cowboy named Bo in love with an 18-year-old singer, Cherie, played by Tuesday Weld. The 26-week series, which starred Marilyn Maxwell as the owner of a diner in fictitious Sunrise, Colorado, aired a half-hour after Follow the Sun. He would star again with Weld in his film debut, 1961's Wild in the Country, with Elvis Presley.

In 1963-1964, Lockwood starred as a young U.S. Marine second lieutenant named william T. ("Bill") Rice in the NBC series The Lieutenant. This drama, about the peacetime Marines, was produced by the creators of Star Trek (Gene Roddenberry) and The Man from U.N.C.L.E. (Norman Felton). The series co-starred Robert Vaughn as Lieutenant Rice's immediate superior, Captain Raymond Rambridge. Despite moderately good reviews, The Lieutenant's Saturday night time slot, opposite CBS' Jackie Gleason's American Scene Magazine, caused its cancellation after 29 episodes. In 1964, Lockwood guest-starred as Major Gus Denver in the first season of 12 O'Clock High, in episode 9, "Appointment at Liege", and again in 1965 in episode 29, "V For Vendetta". He also guest-starred as Lt. Josh McGraw in season 2, episode 4, "The Idolator" of 12 O'Clock High.

Shortly afterwards, Lockwood starred in another NBC television series The Kraft Mystery Theater (also known as Crisis) in an episode titled "Connery's Hands". He was cast opposite Sally Kellerman, with whom he would soon appear again as Helmsman Gary Mitchell in the second Star Trek pilot "Where No Man Has Gone Before" (1965) in which their characters develop god-like powers.

In 1966, Lockwood guest starred as Clint Bethard in the episode "Reunion" of ABC's The Legend of Jesse James, starring Christopher Jones in the title role of Jesse James. That same year, Lockwood appeared as Danny Hamil on the episode "Day of Thunder" of the NBC drama The Long, Hot Summer, based loosely on the works of william Faulkner. He appeared twice in 1966 as Jim Stark in the two-part episode "The Raid" of CBS' Gunsmoke with James Arness. He is well-known among science fiction fans for his role in 2001: A Space Odyssey (1968) as Dr. Frank Poole.

Lockwood co-starred with Stefanie Powers (then his wife) in an episode of ABC's Love, American Style as a newlywed who gets his mouth stuck around a doorknob. In 1983, he guest starred in the series Hart to Hart ("Emily by Hart") with Robert Wagner and Powers, by now his ex-wife.