HMS TALISMAN carried out patrols in home waters, in the Bay of Biscay and from Halifax, Nova Scotia was sent to the Mediterranean to join the 1 Submarine Flotilla based at Alexandria on 5 July 1941. At the beginning of August 1942, HMS TALISMAN (Lt Cdr M Willmott) sailed from the Holy Loch to deploy to the Mediterranean. Whilst on passage through the Bay of Biscay, she was attacked by Allied aircraft and seriously damaged. After a month in Gibraltar undergoing repairs, she sailed on 10 September with supplies for Malta. Five days later she reported sighting the Italian submarine ALABASTRO to the North of Cape Bougaroun, Algeria. As a result of her report, this submarine was sunk by a Sunderland bomber of 202 squadron.

Nothing further was heard from TALISMAN. It is believed that she struck a mine in the Sicilian Channel. The Italians claim to have sunk a submarine on 17 September to the North West of Malta. This may also have been TALISMAN.