In January 1941 Janus assisted with convoy operations between Malta and Piraeus. In March Janus was involved in the battle of Cape Matapan, whilst a unit of the 14th DD Flotilla, under Captain Mack aboard HMS Jervis. On April 10th, the 14th DD Flotilla was detached for duties in the Central Mediterranean, based on Malta, where other craft were already stationed to harass the enemy shipping route to North Africa. On the 15th, whilst patrolling an area near the Kerkenah Islands, Janus and the destroyers HMS Jervis, HMS Nubian and HMS Mohawk spotted an Italian convoy escorted by three Italian destroyers, within minutes the convoy escorts had been destroyed, but the Italian had been lucky to have managed to release a salvo of torpedoes, which sank the destroyer Mohawk. The convoy comprising five merchant ships was completely destroyed. Later the same month Janus with three other destroyers, put to sea from Malta on the 23rd they encountered the armed Italian motor ship Ego which they sank, the German convoy they were seeking however, managed to evade them. On May 20th, Germany launched her attack on the Island of Crete. Patrolling the western sector of the Island was a force under Rear Admiral Glennie. Janus was a member of this force which consisted of cruisers HMS Dido, HMS Ajax and HMS Orion and destroyers HMS Isis, HMS Imperial and HMS Kimberley. Before midnight on the 21st, Glennie had been warned of the approach of a German troop convoy. The enemy convoy consisted of a number of caques-motorised schooners-and small steamers, escorted by one Italian torpedo boat. Once the convoy had been intercepted the Italian escort was soon put out of action and the convoy was obliterated, it was estimated that about 4,000 German troops perished. On the 28th, Janus with HMS Jervis and HMS Hasty sailed from Alexandria to assist with the evacuation of troops from Crete, the pick up point being the little fishing village of Sphakia.

During June – July 1941 British and Gaulist troops occupied Syria against strong French resistance, two large French destroyers, Guepard and Valmy engaged and shelled Janus off Sidon. Janus received five heavy hits, which killed or wounded all on the bridge, her commanding officer miraculously escaped injury. The damage disabled the destroyer so, that she had to heave-to for repairs. In August, the damaged destroyer arrived at Simonstown, South Africa and was docked in the Selborne dry dock, where her damage was surveyed. The rudder was un-shipped, along with the forward boiler and aft torpedo tubes. In October - November she was placed into wet dock for the removal of her gun mountings. During February – March 1942 Janus was re-placed into the wet dock, where she underwent an inclination experiment.

In December 1942 Janus in company with HMS Javelin, HMS Jervis and HMS Kelvin surprised the Italian torpedo boat Lupo, which was rescuing survivors from the freighter Veloce off Kerkennah and sank it.

On 20 January 1944 Janus was involved in the landings of Anzio.  HMS Jervis and some smaller craft. The loss of this destroyer was a sad blow. She and Jervis had fired over 500 rounds of 4.7\", of the first two days of Anzio, a figure typical of many destroyers which indicated the enormous amount of help given by these ships during those critical days in Italy.

The ships badge can still be seen proudly displayed on the side of the Selborne dry dock wall.