On 15 September, in preparation for the assault on Leyte, "Twiggs" departed Pearl Harbor as a member of Destroyer Squadron 49 (DesRon 49), screening Task Group 79.2 (TG 79.2), Transport Attack Group "Baker", which steamed via Eniwetok for Manus in the Admiralty Islands. After final preparations for the impending invasion, she departed Seeadler Harbor on 14 October. Arriving off Leyte on 20 October, "Twiggs" helped to provide antiaircraft protection for the transports during the landings. In the following days of heavy enemy air activity, she continued to support the invasion and, on one occasion, rescued a downed flier from "Petrof Bay" (CVE-80). "Twiggs" departed Leyte on 25 October, steamed via Mios Woendi Island to Manus, and arrived at Seeadler Harbor on 1 November.