Shortly after being completed as Flotilla Leader, HMS Laforey (G 99) joined Force H at Gibraltar and escorted a Malta convoy. The destroyer took part in the most Malta operations in 1941 and 1942. On one of this operations, HMS Ark Royal (91) was torpedoed on 13 Nov 1941 by U-81 (Guggenberger). The aircraft carrier lost all power and the destroyer went alongside to provide power and assist the rescue and salvage parties, but the carrier foundered shortly before reaching Gibraltar. Similarly, the destroyer rescued survivors from HMS Eagle (94), which had been torpedoed and sunk by U-73 (Rosenbaum) on 12 Aug 1942 during another Malta operation. Between these operations, in May 1942, HMS Laforey (G 99) participated in the landings at Diego Suarez, Madagascar. In December 1942, the destroyer escorted the convoy KMF-5, when the Strathallan was torpedoed on 21 December by U-562 (Hamm). The destroyer picked up many survivors and took the ship in tow, but she foundered shortly before reaching Oran.
In the spring of 1943, HMS Laforey (G 99) undertook shore bombardments in Tunisia and participated in the blockade of the Cape Bon area to prevent the escape of the German Army to Sicily. In June 1943, the vessel took part in the bombardment and capture of Pantellaria and Lampedusa and a month later participated in the landings in Sicily. On 23 Jul 1943, the Italian submarine Ascianghi (STV Mario Fiorini) was sunk by depth charges from HMS Laforey (G 99) and HMS Eclipse (H 08) near Augusta. In September 1943, the destroyer participated in the landing at Salerno and was hit by a shore battery. The engine room was damaged, but the ship remained on patrol at a reduced speed. Between October 1943 and January 1944, she took part in various bombardments of enemy positions on the west coast of Italy.

HMS Laforey (G 99) earned the following battle honours: Malta Convoys 1941-42, Diego Suarez 1942, Atlantic 1942, Sicily 1943, Salerno 1943, Mediterranean 1943-44, Anzio 1944.

On 29 March 1944, U-223 was located by asdic from HMS Ulster (R 83), which was carrying out a routine Anti-Submarine sweep together with two other destroyers of the 14th Flotilla, HMS Laforey (G 99) and HMS Tumult (R 11). The U-boat was heavily depth-charged, but managed to carry out many evasive manoeuvres in an attempt to evade destruction. In the early morning on 30 March, the U-boat was forced to surface and was attacked by the destroyers with gunfire, which now included HMS Hambledon (L 37), HMS Blencathra (L 24) and HMS Wilton (L 128), which had replaced HMS Ulster (R 83). Shortly before being sunk, U-223 fired a Gnat and hit HMS Laforey (G 99), which sank about 60 miles northeast of Palermo, Sicily. Among the 189 who lost their lives was the commanding officer of the destroyer and the 14th Flotilla, Capt H.T. Armstrong, DSO, DSC, RN.