Prior to the entry of the United States into World War II, the destroyer saw over a year's service opposing the spread of Axis power.

In addition to Neutrality Patrol in the Caribbean and North Atlantic convoy duty, she was escort on two diplomatic voyages in January 1941.

Steaming at first between Greenock, Scotland and the Mediterranean, Madison was with Wasp when that aircraft carrier delivered Supermarine Spitfires to the besieged island of Malta.

These planes enabled the residents to hold on to their position, preventing Axis air supremacy in the western Mediterranean, and providing a future logistics base for the Allies.

On 2 November, she departed New York City for Casablanca with convoy UGF 2 of troops and supplies to support the initial invasion of north Africa.

For the remainder of the year, she continued to escort convoys of tankers and other types of merchant ships between the Netherlands West Indies, New York, north Africa, and various United Kingdom and Mediterranean ports.

During Operation Dragoon, Madison, on antisubmarine patrol and fire support duty on 10 September, made four certain kills of human torpedoes and one probable.