Her first war patrol began on March 19, 1945.  She refueled at Saipan, then headed for an area south of Bungo Suido (Bungo Straits).  On April 11, Lionfish narrowly evaded two torpedos fired at her by a submerged Japanese submarine.  Twenty days later she battle-surfaced on a 100-ton schooner and quickly reduced it to a flaming hulk.  From there whe took up lifeguard duty off of Shanghai, China.  On May 9, she rendezvoused with the USS Ray and took aboard a group of B-29 survivors and deposited them at the base in Saipan.  After topping off with fuel, she headed for Midway to be refitted, arriving on 22 May 1945.

Lionfish initiated her second foray into the war zone on 20 June under the direction of Cdr. Bricker Ganyard, again bound for Bungo Suido.  On 10 July she ambushed and torpedoed an I-class Japanese submarine.  After regaining periscope depth, her captain saw only a cloud of smoke in the direction of her victim.  Shortly afterward, Lionfish's crew heard loud breaking-up noises and felt confident that the sub had been sunk (this could not be positively confirmed from postwar records).

In a matter of days, Lcdr Spruance launched similar attacks on two more enemy submarines.  Both failed, one due to an erroneous TDC setting.  With no torpedoes left, she was assigned lifeguard duty until July 18, when she departed for Tanapag Harbor, Saipan for more fuel and torpedoes.

She departed Saipan on 22 July and ventured forth to resume lifeguard duty off the Nansei Shoto and Honshu, Japan.  She remained in this area until hostilities ended on 15 August, then headed for Midway, arriving on August 22, 1945.  Eight days later, Lionfish left for the West Coast, arriving at Mare Island.

She was decommissioned on 16 January and entered the Pacific Reserve Fleet.  Lionfish was awarded one battle star for her valarous World War II service.