On 26 October 1942, Lieutenant Shirane participated in the Battle of the Santa Cruz Islands. As the senior fighter leader in Lieutenant Commander Shigeharu Murata's first strike on the US carriers, he led 21 A6M Zeros (including eight from "Zuikaku") as an escort for 21 Aichi D3A dive bombers and 20 Nakajima B5N torpedo bombers. However, on the way to the US fleet, nine "Zuihō" Zeros led by Lieutenant Saneyasu Hidaka broke off to attack an incoming US strike force on a reciprocal course, reducing the escort to twelve Zeros. Shirane's own "Zuikaku" fighters were involved in intense aerial combat over the US fleet, where they shot down several Grumman F4F Wildcat fighters and lost two of their own Zeros in return. After US dive bombers damaged "Shōkaku" and "Zuihō", the remaining Japanese carriers, "Zuikaku" and "Jun'yō", launched follow-up strikes against the US carriers. Shirane again led Zeros to escort the bombers.