The boat was ordered to operate against enemy aircraft carriers that entered the Western Mediterranean from Gibraltar to launch fighter aircraft for Malta.

On 1 May, the starboard diesel engine of U-375 broke down but the boat nevertheless participated in the rescue operation for U-573, which was badly damaged during an air attack in the afternoon. No contact was made with the U-boat in distress during the night and the next morning she reached the port of Cartagena in neutral Spain under own power. However, the Allied forces still searching for the crippled U-boat located U-375 and U-74 during the afternoon on 2 May and sank the latter. U-375 managed to escape, but had to abort the patrol as the defective diesel engine could not be repaired at sea.