In 1938, he became Chief of Staff of the IJA 5th Division, and was promoted to major general the following year when he was re-assigned to the Kwangtung Army as chief of cavalry operations. He became a lieutenant general in 1942.
In April 1944, Saito was appointed commander of the IJA 43rd Division at the time of its deployment to Saipan. As Japan had lost control of the sea lanes by this time in the Pacific War, the division suffered heavy casualties due to submarine attacks on its transports during the move. Saito was overall commander of all Japanese forces on Saipan, although he had no actual combat experience, and was not even actually the senior Japanese officer on the island. Admiral Chuichi Nagumo, commander of the Central Pacific Area Fleet was also on the island, and was consulted frequently by Saito.
The Battle of Saipan began on 15 June 1944. Without possibility of resupply, the situation was hopeless for the defenders, but Saito was determined to fight to the last man, as he was aware that the fall of Saipan would place the Japanese home islands within range of American strategic bombers. The Japanese used the many caves in the volcanic landscape to delay the attackers, by hiding during the day and making sorties at night. The Americans gradually developed tactics for clearing the caves by using flamethrower teams supported by artillery and machine guns. By 7 July, the Japanese had nowhere to retreat. Over Nagumo's objections, Saito made plans for a final suicidal banzai charge. On the fate of the remaining civilians on the island, Saito said, "There is no longer any distinction between civilians and troops. It would be better for them to join in the attack with bamboo spears than be captured." But by 16:15 on 9 July, American commander in chief Admiral Turner announced that Saipan was officially secured. Saito, wounded by shrapnel, committed ritual suicide in a cave at dawn on 10 July, with his adjutant shooting him in the head after he had disemboweled himself.