After training at New London, Connecticut, and work on an experimental ordnance project at Key West, Florida, Quillback departed for Pearl Harbor and her maiden war patrol, off the coast of Kyūshū.

During this patrol, from 30 May to 24 July 1945, she destroyed a Japanese suicide motorboat and rescued one aviator from the water only a half mile from the heavily armed shore.

From 1945 to 1951, she operated with the Submarine School in a training capacity and as an experimental unit of the Naval Underwater Sound Laboratory.

In April 1951, Quillback departed New London for a six-month tour of duty with the Sixth Fleet in the Mediterranean Sea.

There in local operations, with occasional trips to Guantanamo Bay, she assisted the Fleet Training Group in Destroyer ASW indoctrination.

Experimental torpedo research and development projects were assigned to Quillback in 1965 until she deployed to Guantanamo Bay in June.