Flusser sailed from New York 1 December 1936 for a shakedown cruise which found her operating with Squadron 40-T, a unit formed to protect American interests in the Western Mediterranean during the Spanish Civil War.

On 16 July, she arrived at San Diego, California, her base for Pacific and Caribbean operations until October 1939, aside from a 2-week visit to Washington earlier that year.

Based at Pearl Harbor, she took part in intensive training operations with ships of all types, and on 5 December 1941 put to sea screening Lexington (CV-2).

Her constant activity in the New Guinea area made a west coast overhaul imperative, and she received this at Mare Island between April and June.

Continuing her support of the Philippines operation, Flusser escorted reinforcement convoys to Leyte from Hollandia, and on 4 December 1944, received damage from the near miss of a Japanese suicide plane.

The destroyer sailed from Leyte 6 December to cover the landings at Ormoc Bay, and next day her group was attacked by the first of many waves of suicide planes.

Her officers served on teams inspecting Japanese naval and merchant shipping at Sasebo until 29 October, when the destroyer departed for San Diego, arriving 19 November.