In May 1940 transferred to the Red Sea. Pennant number for visual signalling purposes changed to G64. In June took part in the sinking of the Italian submarine Torricelli off Perim Island, and later attacked the Italian submarine Perla.

On 2 March 1941 located the Italian destroyers Pantera and Tigre aground south of Jeddah which, having been scuttled, were destroyed by gunfire and air attack.

On 17 March supported landings at Berbera.

In April 1941 Kingston was deployed to Alexandria to join the Eastern Mediterranean Fleet, where it was involved in the evacuation of Allied troops from mainland Greece to Crete in April.

On 20 May deployed as part of Force C to Battle of Crete.

On 21 May Force C intercepted a convoy of 20 troop carrying caiques escorted by the Italian torpedo boat Lupo heading for Crete. Ten of the caiques were sunk and the landing prevented, but Kingston suffered minor damage from return fire by Lupo.

On 22 May Force C was sent to the Aegean through the Kaso strait to intercept a further invasion convoy of 30 caiques. One detached caique was sunk and, though there was no main attack on the convoy, the Germans were forced to abort the attempt to reach Crete. Force C suffered major damage from air attacks which continued when they joined up with Force A1 at the Kithera channel. Kingston and Kandahar were sent to pick up survivors when the destroyer Greyhound was sunk. Later the same day the cruisers Gloucester and Fiji were sunk by air attacks, and on 23 May Kingston and Kandahar returned and rescued 523 survivors.

Returned to Alexandria on 24 May, and taken in hand for repairs.

In 1941 the after set of torpedo-tubes were replaced by a 4-inch AA gun.

Kingston was engaged on defensive convoy duties to Tobruk and often as part of the escort for Breconshire on runs to Malta. Also was in action against enemy convoys, and against the Vichy French in Syria.

On 17 December 1941 took part in brief engagement with the Italian Fleet, known as the 1st Battle of Sirte.

On 22 March 1942 Kingston took part in the Second Battle of Sirte, where, as the destroyers turned to fire their torpedoes on the Italian battle fleet, she was hit by a 15-inch shell fired by the Italian battleship Littorio which passed right through the ship and burst outside her; despite this, she fired three torpedoes. Fifteen men of her crew were killed in this incident, which left the destroyer temporarily dead in the water, her whaler torn apart, her anti-aircraft guns, searchlight tower and torpedo launchers obliterated by the explosion. With an engine in flames and a flooded boiler, she managed however to recover speed, reaching Malta the next day.

Whilst in dock at Malta repairing damage from this encounter, Kingston was attacked by German aircraft and on 5 April was further damaged by a near miss. On 8 April she was hit by a bomb, forwards. This penetrated through the decks and passed out of the ships bottom without exploding. But now the destroyer needed to go into dock for underwater repairs. On 9 April she was placed in No. 4 dock, but remained afloat. By 11 April she was still afloat in the dock. - perhaps plates bent outwards by the passage of the bomb through the bottom made it impossible to dock-down and these plates were being burnt away by divers. At about 17.30 on 11 April 1942 she was hit on the port side amidships in the area of the bulkhead between the engine-room and the gearing-room. She rolled over on her port side and sank in the dock. The ship was declared a Total Constructive Loss. On 21 January 1943 the No. 4 dock was dried-out. The damaged midships part of the destroyer was scrapped, thus separating the destroyer in two sections. Dummy bulkheads were fitted to make the two sections floatable while an amount of the superstructure was burnt away. The two sections of the Kingston were floated out of the dock on 5 April 1943 and in June were scuttled as a blockship between the Selmun headland and Selmunett Island (St Paul's Island) in northern Malta in the preparations for making a safe anchorage before the invasion of Sicily. In the early 1950s the two sections of the Kingston were scrapped, where sunk, by Italian shipbreakers.

On 4 April 1942 a bomb fell directly at the entrance of the Corradino tunnel. Among those killed by the blast were three officers of Kingston Commander Peter (or Philip) Somerville DSO., Lieut. P. Hague and Sub. Lt. J. Carter, as well as five other sailors of the destroyer. Cdr. Somerville is buried at the Mtarfa Military Cemetery.