The squadron arrived at its combat station, Manduria Airfield, Italy, in early January 1944 and began engaging in the strategic bombing campaign against Germany, primarily striking targets in Austria, Czechoslovakia, France, Germany, Hungary, Italy, and the Balkans.
 The squadron's first mission was flown against Mostar Airfield, Yugoslavia on 8 January.
Targets included aircraft factories and assembly plants, oil refineries, marshalling yards, airfields and storage areas.
Shortly after arriving in theater, the squadron participated in Big Week, attacking aircraft factories at Regensburg, Germany and Steyr, Austria.
 It was awarded a Distinguished Unit Citation (DUC) for its attack on the Messerschmitt factory at Regensburg on 25 February, despite bad weather, heavy flak in the target area and enroute attacks by enemy interceptor aircraft.
 The 450th Group led the 47th Bombardment Wing on the attack.
The 721st earned a second DUC for an attack on rail yards near Ploesti on 5 April, when it fought its way through "relentless" attacks by enemy aircraft to reach the target.
The rail yards were a vital link in the transportation of petroleum products from the Ploesti refineries to the eastern front.
The 450th Group again led the 47th Wing on this mission.

During the spring of 1944, the squadron flew missions for Operation Strangle, the effort to choke off supplies for Axis military in Italy through air interdiction.
 The squadron also supported Operation Dragoon, the invasion of southern France in September 1944 by attacking troop concentrations, lines of communications and enemy coastal defenses.
 In addition, it conducted missions to support the Red Army advance through the Balkans and Allied advances in Italy.

The squadron returned to the United States in May 1945, assembling at Sioux Falls Army Air Field, South Dakota at the end of the month.
 It moved to Harvard Army Air Field, Nebraska in July and trained with the Boeing B-29 Superfortress, however after V-J Day in August the squadron inactivated on 15 October.
The squadron arrived at its combat station, Manduria Airfield, Italy, in early January 1944 and began engaging in the strategic bombing campaign against Germany, primarily striking targets in Austria, Czechoslovakia, France, Germany, Hungary, Italy, and the Balkans.  The squadron's first mission was flown against Mostar Airfield, Yugoslavia on 8 January. Targets included aircraft factories and assembly plants, oil refineries, marshalling yards, airfields and storage areas. Shortly after arriving in theater, the squadron participated in Big Week, attacking aircraft factories at Regensburg, Germany and Steyr, Austria.  It was awarded a Distinguished Unit Citation (DUC) for its attack on the Messerschmitt factory at Regensburg on 25 February, despite bad weather, heavy flak in the target area and enroute attacks by enemy interceptor aircraft.  The 450th Group led the 47th Bombardment Wing on the attack. The 721st earned a second DUC for an attack on rail yards near Ploesti on 5 April, when it fought its way through "relentless" attacks by enemy aircraft to reach the target. The rail yards were a vital link in the transportation of petroleum products from the Ploesti refineries to the eastern front. The 450th Group again led the 47th Wing on this mission.
During the spring of 1944, the squadron flew missions for Operation Strangle, the effort to choke off supplies for Axis military in Italy through air interdiction.  The squadron also supported Operation Dragoon, the invasion of southern France in September 1944 by attacking troop concentrations, lines of communications and enemy coastal defenses.  In addition, it conducted missions to support the Red Army advance through the Balkans and Allied advances in Italy.
The squadron returned to the United States in May 1945, assembling at Sioux Falls Army Air Field, South Dakota at the end of the month.  It moved to Harvard Army Air Field, Nebraska in July and trained with the Boeing B-29 Superfortress, however after V-J Day in August the squadron inactivated on 15 October.
721st Tactical Fighter Squadron