On November 18 1941, Isokaze departed alongside the rest of the 17th destroyer division to escort the Kido Butai for a mysterious mission, which turned out to be the attack on Pearl Harbor which commenced on December 7, then returned to Kure on the 24rd.

On the 7th, Isokaze took part in the bombardment of Christmas Island, then escorted the Kido Butai during the Indian Ocean Raid, and finally arrived back at Kure on April 27, and entered drydock from May 5-15.

After surviving an encounter with a B-17 bomber, Isokaze escorted a convoy to Rabaul, then on September 11 attempted a troop transport mission, but returned to Rabaul after her consort, the Yayoi, was sunk by B-17 bombers, before seeing several more successful troop transport mission, then in October engaged in patrol duty before escorting carriers at the battle of Santa Cruz on the 26th, then returned to Truk on the 30th.

From November 2-7, Isokaze escorted damaged ships to Sasebo for repairs, before being drydocked herself until the 18th, then departed for Yokosuka for troop transport and training missions.

At the start of January 1943, Isokaze survived B-17 bomber attacks, then departed Rabaul to escort a large troop convoy to Lae and back.

Isokaze successfully chased off the enemy destroyers with the help of the other Japanese ships, and in turn took a single 5-inch (127 mm) shell hit, causing minor damage.

Isokaze joined her sistership Urakaze in fending off Tunny with depth charge attacks, then escorted the battleship to repairs.

This came at the protest of Tanikaze's crew, as Yukikaze was beginning to gain a reputation as a "luck vampire", surviving battles completely undamaged as where other ships operating with her were damaged or sunk.

[4] In early April, Isokaze escorted a convoy to Lingga, during which she badly damaged the submarine USS Scamp with depth charges, then spend the rest on the month on training duties, and on May 12 finally departed to escort Japanese warships to Tawitawi, then spend the rest of the month on patrol duties.

After being drydocked for maintenance, Isokaze arrived at Brunei on October 20, and two days later departed as part of Admiral Kurita's center force for Operation Sho-Go, better known as the battle of Leyte Gulf, with the goal of attacking allied troop convoys destined for the Philippines.

Isokaze escaped undamaged, but several other ships were damaged, and the battleship Musashi, victim of 17 bombs and 19-20 torpedoes, sank over nine hours.

Captain Maeda, while half considering it, ultimately gave into his conscious and ordered an attack off, but Isokaze steamed off without rescuing survivors.

After the Japanese ships retreated, Isokaze evaded further air attacks without damage, and returned to Brunei on the 28th, enroute being refueled by the battleship Nagato.

Not wanting to disappoint their ruler, the Japanese hatched up a plan, the battleship Yamato was to depart on a one way mission to beach herself on the island to act as a stationary, unsinkable gun fortress to sink US troop ships.

Isokaze was one of nine escorts tasked with ensuring Yamato made it to her destination, alongside seven other destroyers and the light cruiser Yahagi.

Isokaze managed to evade the first several attacks, until noticing Yahagi dead in the water due to a torpedo hit that destroyed her engine room.