In its combat debut in Tunisia in 1943 during the North African campaign, the M10 was successful as its M7 3-inch gun could destroy most German tanks then in service. The M10's heavy chassis did not conform to the quickly evolving tank destroyer doctrine of employing very light high-speed vehicles, and starting in mid-1944 it began to be supplemented by the 76mm Gun Motor Carriage M18 "Hellcat". Later in the Battle of Normandy, the M10's gun proved to be ineffective against the frontal armor of the newer German Tiger and Panther tanks unless firing HVAP rounds, but was effective against the most common tanks such as the Panzer IV medium tank and other lighter vehicles and self-propelled guns. Tank destroyer units had been supplemented with 90mm towed guns in partial anticipation of heavier German tanks, but their lack of mobility made employing them difficult. By the fall of 1944, the improved 90mm Gun Motor Carriage M36 began to arrive in Europe as well. In the Pacific war, US Army M10s were used for infantry support, but were unpopular due to their open-topped turrets, which made them more vulnerable than a fully enclosed tank to Japanese close-in infantry attacks.
Approximately 54 M10s were supplied to the Soviet Union, though their use by the Red Army is largely unrecorded. The M10 also equipped units of the Free French Army; one M10 named Sirocco, part of the Régiment Blindé de Fusiliers Marins composed of French sailors, famously disabled a Panther on the Place de la Concorde during the liberation of Paris.
The British were supplied with M10 and M10A1 vehicles. British M10s were designated as (Gun) 3 inch Self Propelled (3in SP) or "M10 3 in SP" and, as with all British self-propelled anti-tank guns, were operated by Royal Artillery units. They saw action in Italy and France. Many in France were upgunned with the more effective 17-pounder gun (as the 17pdr SP Achilles) from 1944 onwards. These were designated "17pdr SP Achilles Mk IC" for the M10 and "17pdr SP Achilles Mk IIC" for the M10A1. As well as service in the British forces in North West Europe they were retained post-war. Those not upgunned were stripped of their turrets and used as artillery tractors.
The M10's open-topped turret left the crew vulnerable to artillery and mortar fire and fragments. The crew is also exposed to long distance sniper fire and infantry close assault, such as thrown grenades, or attacks from upper story windows, especially in urban combat and wooded areas. Based on US infantry doctrine, this was not considered a major flaw as American infantry was supposed to have carried significant support firepower when supporting the vehicles in the type of combat that made them most vulnerable. However, the open-topped turret gave excellent visibility, which was valuable for a vehicle that was tasked with finding enemy armored vehicles and other targets. The open top also made escape easier when the vehicle was hit and improved communications with accompanying infantry.
Though other nations such as the Soviet Union and Germany deployed TDs according to the same inter-war era mobility doctrine as the US, their TDs were low, slow vehicles with very large guns in limited traverse case-mates. In order to compensate for its deficiencies, some individual US crews improvised overhead turret armor in Normandy to protect against mortars and grenades. One M10 was photographed with an almost complete roof fitted to a raised edge which had vision slits, all manufactured out of captured German plating. In UK service, one M10 in the 86th Anti-Tank Regiment (XII Corps) in Normandy drove back out of action three separate times with the entire turret crew dead. Two turret crews had been killed by 88mm air bursts or mortars exploding in treetops, one crew were killed by a direct hit through the turret. The same driver survived each time. When this driver was placed with a new crew, his fourth, he was declared to be a 'Jonah' (bad luck) and they refused to drive with him. He was transferred to another unit and told to keep quiet about his history.
By the end of the war its armor was clearly too thin to provide protection from the newer German tanks, anti-tank guns, and infantry anti-tank weaponry. M10s in Europe were fitted with layers of sandbags or baulks of timber attached to front and side armor to detonate Panzerschreck rockets and Panzerfausts before they struck the main plate. The M10 had a very slow turret rotation speed, as the turret traverse was unpowered and the crew had to hand-crank the turret around. It took approximately two minutes to rotate a full 360 degrees. However, this slow rotation speed may have been again more a theoretical flaw than real as compared to German armored fighting vehicles, as the M10 was generally more mobile than its turreted opponents in the most common tactical situations in Europe and had far better traverse than turretless German tank destroyers with virtually no traverse and which were much less mobile. The German Panzer IV Ausf. J, produced exclusively in 1944-45 also had manual-only turret traverse, which was twice as fast as the M10, with the Tiger I having the same speed as the J's. Panthers and Tiger IIs could traverse four times as fast as the M10. It was more important that US AFVs would generally operate in greater numbers in tactical situations, and therefore had more firing angles and greater firepower in battle than their German opponents. Consequently, the Germans in the West lost more AFVs than they could afford. The Western European terrain permitted very little in the way of long distance tank engagements where the heavy German tank's high velocity guns and thick frontal armor could be used to their advantage. The lack of German AFV numbers is indicated by the fact that U.S. tank destroyers fired many more high-explosive shells than anti-tank ammunition, indicating that they were employed much like the tanks they were assigned to support.
In UK service, the M10 was normally issued to four-battery regiments of the Royal Artillery. Typically they were re-armed with the more powerful 17-pounder gun and, typically, two batteries had M10s while two batteries had the towed 17-pounder gun. One tactical theory was that the two towed batteries would form a gun line while an M10 battery remained mobile on each flank and drove or led enemy tanks on to the static gun line. In practice, UK batteries were frequently separated in Normandy, with the M10 batteries often being seconded to British tank brigades which operated within infantry divisions; these brigades were equipped with Churchill tanks with the general purpose 75 mm gun.
In the final analysis, the M10, although it was clearly not a superior weapons system in Europe in 1944-45, proved to be useful, effective, and survivable enough to maintain unit strengths through replacement and repair.
The most decorated American soldier, Audie Murphy, earned his Medal of Honor at the Battle of the Colmar Pocket, when he used the heavy machine gun of an abandoned and burning M10 to repel German infantry. He was reportedly very disappointed when an M10 was not available for his reenactment of the event in the post-war film To Hell and Back and he had to use a Sherman in its place.
Ten German Panther tanks were modified to look like M10s in the Ardennes Offensive.