On 26 November 1941, HNMS Isaac Sweers was allocated to the 19th Destroyer Flotilla, Group I and conducted anti-submarine patrols west of Gibraltar. On 11 December, the ship was scheduled to return to England for an overhaul, but received orders to leave Gibraltar for the Eastern Mediterranean instead. The destroyer was attached to the 4th Destroyer Flotilla under Cdr Stokes on board the British destroyer HMS Sikh and left Gibraltar in the evening. During the night, they received a radio message from a patrolling Wellington aircraft about two Italian light cruiser steaming southwards. The destroyers steamed with 30 knots through the Skerki-channel and spotted several lightflashes and vague silhouettes near Cape Bon at about 02.00 hours. The flotilla rounded the Cape and sighted the two approaching Italian light cruisers Alberico da Barbiano and Alberto di Giussano. HMS Sikh was leading the group, then HMS Legion, HMS Maori and finally HNMS Isaac Sweers. Two of the four fired torpedoes from the leading destroyer struck the first cruiser, which was also hit by one torpedo of and gunfire from HMS Legion and another torpedo from HMS Maori. The cruiser was ablaze and quickly started to sink. The second cruiser opened fire but missed and was then sunk by one torpedo from HMS Legion and the concentrated gunfire by all destroyers. The HNMS Isaac Sweers then encountered the Italian torpedoboat Cigno, which was attacked by gunfire and missed with four torpedoes. The destroyer reported also the sinking of an Italian MTB, but this was not confirmed by the Italian Admiralty. The Allied destroyers arrived at Malta on 13 December.

A few days later, the destroyers left Malta together with the Force K to met the fast transport Breconshire, which had left Alexandria on the 15 December. In the early morning of 17 December, they met the transport and her escort. The convoy was attacked by aircraft numerous times between 13.00 and 18.00 hours, but sustained no losses. In the evening, a Italian fleet of four battleships, numerous cruisers and destroyers approached the convoy and opened a well-aimed fire at about 14 miles. At the same time the aircraft attacks continued and one was shot down by the Dutch destroyer. The convoy changed course to the south and the destroyers and the cruisers of Force K later turned around to attack the enemy fleet with torpedoes. But the Italians were already steaming back to their harbours. The convoy reached Malta on 18/19 December, but the Dutch destroyer left Malta for Alexandria soon afterwards. On 24 December, Cdr W. Harmsen took over the command from Cdr J. Houtsmuller.

On 16 January 1942, HNMS Isaac Sweers left Alexandria with three destroyers to escort the convoy MW-8B, consisting of four merchants, to Malta. At 07.35 hours on 17 January, HMS Gurkha was torpedoed by U-133 (Hesse) and caught fire. HNMS Isaac Sweers towed the destroyer free from the burning oil on the surface and took over the most crew members. The damaged destroyer had to be scuttled. The Dutch destroyer was ordered to put the survivors ashore in Tobruk, arriving in the evening and returned to the convoy at 02.00 hours on 18 January, which arrived at Malta unharmed.

On 23 January, HNMS Isaac Sweers was sent to the Netherlands East Indies, because of the Japanese advances in that area, arriving on 8 February in Colombo, where she went into the drydock for some minor repairs and maintenance. She departed on 28 February, but was ordered back shortly thereafter, because the Netherlands East Indies were already lost and the destroyer was attached on 15 March to the British Eastern Fleet, arriving on 5 April at the Addu Atoll for refueling. The same day, she left together with the Force B to find a Japanese carrier fleet, which was operating in the Indian Ocean. The Japanese attacks on Colombo, Trincomalee and several ships in the Indian Ocean were successful, but the Force B was not able to find the attackers and arrived on 14 April in Bombay. On 30 April, the Force B arrived at the Seychelles and was based at Mombasa on 22 May, while HNMS Isaac Sweers left for England via Durban, Simonstown, Freetown and Gibraltar. On 1 June, the Cdr W. Harmsen was promoted to Captain.

From June to September 1942, the destroyer was overhauled at the Thornycroft Dockyard, Southampton. The .50cal MG´s were replaced by 20mm Oerlikon AA guns and her DC-equipment was augmented. A new Asdic-type was also installed. The overhaul was followed by a practice period in Scapa Flow. In October 1942, the destroyer was part of the escort for the British carrier HMS Furious to Gibraltar. HNMS Isaac Sweers left Gibraltar together with the British destroyers HMS Escapade and HMS Marne for Punta Delgada on the Azores. On 29 October 1942, the destroyers departured for a rendez-vous with the troop convoy KMF-1, part of the Operation Torch, the invasion of North Africa. But the destroyers missed the rendez-vous point as a result of a mistake made in deciphering a signal and remained near Gibraltar until they became part of the Force H. On 11 November, HNMS Isaac Sweers and the British destroyer HMS Porcupine were ordered to pick up the survivors from the troop transport Nieuw Zeeland, which had been sunk by U-380, and take them to Gibraltar. In the evening of 12 November 1942, HNMS Isaac Sweers (Capt. Willem Harmsen, R.Neth.N.) refueled at sea from a fleet oiler of the Force R (two oilers and four armed trawlers). She was ordered to cover the oilers until the morning and then return to the Force H. At 06.15 hours on 13 November, the destroyer was hit by two torpedoes from U-431 on the starboard side in position 37º23'N, 02º12'E. One torpedo struck a oil tank, spreading burning oil over the ship and the water. The second torpedo hit the longroom and officers quarters, killing all 13 officers sleeping there. The survivors were picked up by the British armed trawler HMS Loch Oskaig, which also tried to get alongside the burning ship, but did have to abandon the plan due to the heavy fires and exploding ammunition.

Commanding Officers:
Cdr. Jacques Houtsmuller
29 May 1941 - 30 December 1941

Cdr. Willem Harmsen
Promoted to Capt. on 30 June 1942
30 December 1941 - 13 November 1942

Hit by U-boat
Sunk on 13 Nov, 1942 by U-431 (Dommes).