As part of the United States mobilization during World War II, the 185th Infantry Regiment was federalized at Fresno, California, on 3 March 1941 and moved to Camp San Luis Obispo, California, within two weeks. The regiment trained there for over a year as part of the 40th Division before relocating to Fort Lewis, Washington, on 29 April 1942. From there, the regiment went to San Francisco, California, in August and was shipped to Hawaii the following month. The regiment stayed in Hawaii where it trained in jungle warfare for over a year before being moved forward during January 1944 to the Solomon Islands. From April through December the regiment was employed in combat on New Britain island during the New Britain campaign. Then the regiment landed on Manus Island in December 1944 and invaded the Japanese-held Philippine Islands on 9 January 1945. The regiment participated in various actions of the Philippines Campaign of 1944–45 during the rest of the war, and arrived back at San Francisco, California on 5 April 1946, being inactivated the next day.