The second U-81 was a Type VIIC submarine of the Kriegsmarine. Her keel was laid down 11 May 1940, by Bremer Vulkan, of Bremen-Vegesack. She was commissioned 26 April 1941 with Oberleutnant zur See Friedrich Guggenberger in command. Guggenberger remained in command, receiving a promotion to Kapitänleutnant, until December 1942 when he was relieved by Oblt. Johann-Otto Krieg, who commanded her until the end of her career.
U-81 conducted 17 patrols, sinking 23 ships totalling of 63,289 tons and damaging two others totalling 14,143 tons. On 13 November 1941, she sank the British aircraft carrier HMS Ark Royal in the Mediterranean.