On 20 October 1944, "Isuzu" participated in the Battle of Leyte Gulf as part of Vice Admiral Jisaburō Ozawa's Northern Mobile ("Decoy") Force. In the Battle off Cape Engaño on 25 October 1944 – 26 October 1944 Ozawa's force was attacked by TBM-1C aircraft of VT-21 from Task Group 38.4's aircraft carrier and VT-51 from . The aircraft carrier was hit heavily and "Isuzu" unsuccessfully attempted to take the ship in tow. After "Chitose" sank, "Isuzu" rescued 480 survivors. Later the same day, "Isuzu" attempted to protect the , which was damaged by a second strike by aircraft from "Lexington" and . However, a force of four US cruisers and nine destroyers appeared on scene and sank "Chiyoda" with all hands. While rescuing survivors, "Isuzu" itself came under fire from the American units and 13 crewmembers were killed.