After working up was completed in May 1941, HMS Hermione (74) served with the 2nd Cruiser Squadron in the Home Fleet during the hunt for the German battleship Bismarck. From June 1941 until March 1942 she joined Force H at Gibraltar and participated in many Malta convoy operations in the 1st Cruiser Squadron of the Mediterranean Fleet.

On 2 Aug, 1941, the cruiser rammed and sank the Italian submarine Tembien in the Sicilian Narrows.
In March 1942 she escorted the convoy for Operation Ironclad (the invasion of Madagascar) from Gibraltar to Durban and took part in the occupation of Madagascar in May 1942. The HMS Hermione (74) then became part of the 15th Cruiser Squadron in the Eastern Mediterranean. 

The HMS Hermione (74) (Capt G.N. Oliver, DSO, RN) was part of the Force A, which escorted the convoy MW-11, a supply convoy under Rear Admiral P.J. Vian from Alexandria to Malta in the Operation Vigorous.

At 00.19 hours on 16 Jun, 1942, the cruiser, returning to Alexandria, was hit by a torpedo from U-205 and sank north of Sollum.