The Shrike was first employed during the Vietnam War by the Navy in 1965 using A-4 aircraft. The Air Force adopted the weapon the following year using F-105F and G Thunderchief Wild Weasel SEAD aircraft, and later the F-4 Phantom II in the same role. The range was nominally shorter than the SA-2 Guideline missiles that the system was used against, although it was a great improvement over the early method of attacking SAM sites with rockets and bombs from F-100F Super Sabres. A Shrike was typically lofted about 30 degrees above the horizon at a Fan Song radar some 15 miles (25 km) away for a flight time of 50 seconds. Tactics changed incrementally over the campaigns of 1966 and 1967 until the advent of the AGM-78 Standard ARM. This new weapon allowed launches from significantly longer range with a much easier attack profile, as the ARM could be launched up to 180 degrees off target and still expect a hit and its speed allowed it to travel faster than the SA-2. Even after the AGM-78 entered service, the Weasels still carried the Shrike because the ARM cost about $200,000, while a Shrike cost only $7,000. If USAF pilots expended an ARM they would have to fill out a lengthy form during debriefing. A somewhat standard load for the F-105G was a 650 US gal (2,500 L) centerline fuel tank, two AGM-78s on inboard pylons and two Shrikes on the outboards. The mix varied slightly for jamming pods and the occasional AIM-9 Sidewinder but this was the baseline.
Shrike was involved in a friendly fire incident during a 15 April 1972 airstrike on Haiphong. Two missiles struck USS Worden (CG-18) killing one crewman and injuring nine more. An American pilot apparently interpreted the PIRAZ cruiser's AN/SPG-55 radar as a North Vietnamese SAM site. Worden required ten days shipyard work at the Subic Bay Naval Base to repair the damage.
Although the Shrike missile did not enter regular service with the United Kingdom, it was supplied to the RAF for use in the Falklands War of 1982. RAF Shrikes were fitted to modified Vulcan bombers in order to attack Argentinian radar installations during Operation Black Buck. The main target was a Westinghouse AN/TPS-43 long range 3D radar that the Argentine Air Force deployed during April to guard the Falklands' surrounded airspace. The Argentine operators were aware of the anti-radar missiles and would simply turn it off during the Vulcan's approaches. This radar remained intact during the whole conflict. However, air defences remained operational during the attacks and the Shrikes hit two of the less valuable and rapidly replaced secondary fire control radars. Also, following a Vulcan making an emergency landing at Rio de Janeiro, Brazilian authorities confiscated one Shrike which was not returned.
About 95 AGM-45s were used in 1991 during Desert Storm against Iraqi air defense, mostly by F-4Gs.