Initially assigned to Submarine Division (SubDiv) 19 and then to SubDiv 11, "S-43" completed trials off the Connecticut coast and, in April 1925, moved south to Guantanamo Bay. Thence, she proceeded to the Submarine Base, Coco Solo in the Panama Canal Zone, where she was based for the next two years. Engaged in exercises—individual, division, and fleet—during that period, she was transferred with her division to the Battle Force in July 1927 and based at San Diego, California. From there, she continued her schedule of exercises and fleet problems into the 1930s. Annual overhauls and exercises off southern California were followed by summer operations in Hawaiian waters and autumn patrols and exercises off Mexico.