In October 1943 the first towed battalion - the 805th TD - arrived in Italy. Subsequently the M5 saw combat in the Italian Campaign and in the Northwest Europe. One of the most notable engagements came during the German counterattack on Mortain in August 1944. The 823rd TD, attached to the 30th Infantry Division, played a key role in the successful defence of Saint Barthelemy, destroying fourteen tanks and a number of other vehicles, though at the price of losing eleven of its guns.
In addition to the anti-tank role, the gun was often used to supplement divisional field artillery or to provide direct fire against enemy fortifications (e.g. a combat report from the 614th TD mentioned a two-gun section firing 143 shells at an enemy post, achieving 139 hits)
Although the M5 easily outperformed older anti-tank guns in the US service, it was large and heavy - making it hard to manhandle into position - and its anti-armor characteristics were found to be somewhat disappointing. In part that reputation reflected initial problems with fuses of APCBC/HE shells. The 3 inch APHE round which was based on the naval 3 inch round, had a small charge in the rear of the round which was supposed to explode after penetration of the targeted tank's armor plating. Unfortunately it was discovered that it exploded on impact or shortly after causing the round not to penetrate. It is still a puzzling mystery as to why this problem was never addressed with a better base fuze or even removing the small HE charge in the rear of the round. This was also the problem with the M10 tank destroyer.
APDS round was never developed for the M5; an APCR round existed (see ammunition table below), but it is not clear if it was ever issued to towed TD battalions.
As a result of the aforementioned shortcomings, commanders and troops generally preferred an alternative in form of self-propelled tank destroyers, which offered better mobility and also better protection for their crews.
The greatest test of the TD battalions and their M5 guns came during the Battle of the Bulge. In this battle, towed tank destroyers fought much less successfully and suffered much higher losses than the self-propelled ones. A report from the aforementioned 823rd battalion said that "tank destroyer guns were one by one flanked by enemy tanks and personnel driven from guns by small arms and machine guns fire". Taking the recent combat experience into account, on 11 January 1945 the War Department confirmed a request to convert the towed TD battalions to the self-propelled form. This decision meant gradual removal of the M5 from frontline service, a process that continued until the end of the war in Europe.
Today, the M5 is utilized by the US Army for ceremonial purposes. The Presidential Salute Guns Platoon of The Old Guard currently maintains a battery of ten M5's at Fort Myer for service mainly in the National Capital Region.