At Mare Island Naval Shipyard for overhaul, 7 December 1941, she reported for convoy escort duty on the 15th and on the 17th was en route to Pearl Harbor.

On 1–2 May, the squadron joined with Task Force (TF) 11 and 17 and screened the carriers as their aircraft struck at Tulagi to open the Battle of the Coral Sea.

That afternoon the ships were attacked by land-based aircraft and in driving them off, diverted the Japanese force accomplishing the mission without engaging the enemy and setting the stage for the final action of the Battle of the Coral Sea.

On the 10th the squadron headed for Australia and for almost two months Perkins escorted convoys and patrolled harbour entrances along the coasts of the Coral and Tasman Seas.

On 21 August Perkins, flagship of DesRon 5, led Smith, Conyngham, and Mahan out of Milne Bay to make a sweep of Huon Gulf and shell Finschhafen.

On 4 September Perkins shelled the coast between the Bulu and Buso rivers, covering Allied landings at Red Beach before heading toward Lae.

Finschhafen fell on 2 October and the increase in Allied shipping traffic in Huon Gulf, together with the presence of Japanese submarines, brought Perkins back to escort duty.