On 16 April 1961, six Super Sabres were deployed from Clark Air Base in the Philippines to Don Muang Royal Thai Air Force Base in Thailand for air-defense purposes, the first F-100s to enter combat in Southeast Asia. From that date until their redeployment in 1971, the F-100s were the longest serving U.S. jet fighter-bomber to fight in the Vietnam War. They served as MiG combat air patrol (CAP) escorts for F-105 Thunderchiefs, Misty FACs, and Wild Weasels over North Vietnam, and were then relegated to close air support and ground attacks within South Vietnam.
On 18 August 1964, the first F-100D shot down by ground fire, piloted by 1st Lt Colin A. Clarke, of the 428th TFS; Clarke ejected and survived. On 4 April 1965, as escorts protecting F-105s attacking the Thanh Hoa Bridge, F-100 Super Sabres fought the USAF's first air-to-air jet combat duel in the Vietnam War, in which an F-100 piloted by Captain Donald W. Kilgus of the 416th Fighter Squadron shot down a Vietnam People's Air Force MiG-17, using cannon fire, while another fired AIM-9 Sidewinder missiles. The surviving North Vietnamese pilot confirmed three of the MiG-17s had been shot down. Although recorded by the U.S. Air Force as a probable kill, this represented the first aerial victory by the U.S. Air Force in Vietnam. The small force of four MiG-17s, though, had penetrated the escorting F-100s to claim two F-105s.
The F-100 was soon replaced by the F-4C Phantom II for MiG CAP, which pilots noted suffered for lacking built-in guns for dogfights.