At the end of March 1943, with her sister ships I-177 and I-178, I-180 departed from Truk to patrol off the east coast of Australia. There she torpedoed and sank the Australian merchant ship on 29 April 1943, the Norwegian merchant ship on 5 May 1943, and damaged the Australian merchant vessels Ormiston and Caradale on 12 May 1943.[1]
In mid-July 1943 I-180 was diverted from her patrol to Kolombangara in the Solomon Islands, arriving in the aftermath of the battle and rescuing 21 survivors from the light cruiser .[1]
On 12 October 1943, the Allies launched an air offensive against Rabaul, with 349 aircraft attacking the port and airfields. During the attack I-180 sustained a direct hit which wrecked her superstructure and prevented her from diving. She sailed on the surface back to Sasebo for repairs and was operational again early the next year.[1]
In late March 1944 she sailed from Ominato to patrol off the Aleutian Islands. On 19 April she sank the liberty ship SS John Straub,[1] and almost certainly also sank the Soviet cargo ship Pavlin Vinogradov on 22 April.[2]
Late on 25 April, she was detected while surfaced by the destroyer escort southwest of Chirikof Island. The submarine promptly crash dived, and over the next three hours Gilmore laid down three barrages of Mark 10 "Hedgehog" anti-submarine mortar shells without result, and then two patterns of depth charges, before finally seeing a heavy underwater explosion at 01:12 on 26 April[1] at .[3] On 20 May 1944 I-180 was presumed lost with all hands, and on 10 July 1944 was removed from the Navy List.[1]