The day after the Japanese attack on Pearl Harbor, Talbot got underway in the screen of the aircraft carrier Saratoga and headed for Hawaii.

She arrived at Pearl Harbor exactly a week after the Japanese raid, patrolled off the islands for ten days, and returned to San Diego.

Talbot departed Dutch Harbor on 31 January 1943 to be converted by the Mare Island Navy Yard into a small but fast troopship.

For two months, the APD participated in training exercises with her division and also escorted ships to New Caledonia, New Zealand, Australia, and Guadalcanal.

The two ships embarked troops of the 169th Infantry Regiment at Guadalcanal, and, on 30 June, they were off their assigned beaches when the assault began.

During the landing of assault troops the next morning, a Japanese "long-lance" torpedo sank Strong, one of the destroyers of the bombardment group.

Late in September, she joined Admiral George H. Fort's Southern Attack Force for the conquest of the Treasury Islands.

On 3 November, Talbot called at Noumea to embark reinforcements for troops who, two days before, had landed on the beaches of Bougainville at Empress Augusta Bay.

She arrived on 6 November, disembarked her soldiers, loaded 19 casualties and screened a group of landing ship tanks (LSTs) to Guadalcanal.

Although under constant air attack, Talbot's boats rescued 68 crew members and 106 marine passengers from the stricken ship.

On 28 January, the fast transport embarked elements of the 30th New Zealand Battalion and a group of intelligence and communications specialists of the United States Navy and headed for the Green Islands to participate in a reconnaissance in force.

On 13 February, Talbot reembarked New Zealand troops and sortied with TF 31, the Green Islands Attack Group.

On 17 March, the transport loaded elements of the 2d Battalion, 4th Marines, at Guadalcanal and sailed with the amphibious force to the St. Matthias Islands.

She headed to New Guinea on 4 April to participate in practice landings with the 168nd Army Regimental Combat Team (RCT).

However, she collided with the battleship Pennsylvania during an emergency turn; and the resulting flooding of several of her compartments forced her to return for repairs.

The ship developed engine trouble and anchored in the transport area where an enemy plane dropped a stick of bombs off her port bow, but caused no damage.

The transport departed with a convoy and arrived at Seeadler Harbor on 27 October, where she transferred the demolition team to President Hayes on the last day of the month.

Talbot headed toward Oro Bay, joined George Clymer, escorted her to Cape Gloucester, and returned to Seeadler Harbor on the 8th.

Two days later, she was anchored there, only some 800 yards (732 m) from Mount Hood, when that ammunition ship suddenly exploded and showered her with over 600 pounds (272 kg) of metal and debris.

On 15 December 1944, after the high-speed transport's damage had been repaired at Manus, Talbot got underway and proceeded, via Aitape, to Noemfoor Island to participate in amphibious exercises with the 158th RCT.

Talbot and LSM-331 proceeded to Parece Vela to conduct a survey of the reef and determine the feasibility of erecting a radio, weather, and observation station there.

Five days later, she began antisubmarine patrols south of Kerama Retto and then, on 30 April, joined a convoy for Saipan.