On 1 February 1965, the 12th TFS deployed to DaNang AB, South Vietnam, for combat under control of the 2nd Air Division. A portion of the squadron went to Korat RTAFB, Thailand on 8 February, and on 20 February the remainder of the unit moved to Korat. Combat continued through 15 March 1965 with the 12th completing 279 sorties without the loss of a plane or a pilot. The 12th returned to its home base, but deployed to Korat a second time from 15 June to 25 August 1965, again flying combat sorties under 2AD control. During this deployment the 12th completed 1,520 sorties including strikes, armed reconnaissance, and escort and rescue missions. Five unit aircraft were lost in combat.

Following its second SEA combat tour the squadron returned to Kadena AB and remained there until January 1968, training to maintain combat readiness. However, during the height of the Rolling Thunder campaign in 1966-1967, many squadron aircraft and pilots were loaned to the PCS units performing combat in SEA.

By 15 December 1967, the 12th TFS was the only tactical fighter squadron still assigned to the 18th TFW. It deployed to Osan AB, South Korea, 23 January - 13 June 1968, in response to the seizure of the U.S.S. Pueblo by North Korea.

Returning to Kadena AB in mid June, the 12th continued to maintain a portion of its aircraft and crews at a forward base in Korea until 8 December 1970, and even after that date frequently deployed elements to Korea to meet commitments there. The squadron simultaneously sent many of its pilots to Thailand to fly combat missions, thus keeping them combat ready. A detachment (Det. 1, 12th TFS) was deployed to Korat RTAFB, which would later evolve into the 6010th Wild Weasel Squadron, when complementary F-105G's and crews arrived from Takhli RTAFB as the 355th TFW deactivated.

The Thunderchief days in the 12th TFS were numbered as May 1972 approached. However, the 12th went out in style, by finishing #1 at the 5th Air Force Weapons Meet. An apt parting remark from then-Captain Bob Venkus, one of the 12th TFS pilots: 'Check 12 low for you might catch a glimpse of one of the last Thunderchiefs as it heads for the Guard ramp at a speed just slightly beyond your "Q" limit.'

Today, the 12th Fighter Squadron (FS) is flying out of Elmendorf AFB and is equipped with the F-15C Eagle.