The United States formally entered World War II in December 1941, following Japan's surprise attack on Pearl Harbor in Hawaii. Six months later, Bush enlisted into the U.S. Navy immediately after he graduated from Phillips Academy on his eighteenth birthday. He became a naval aviator, taking training for aircraft carrier operations aboard USS Sable. After completing the 10-month course, he was commissioned as an ensign in the United States Naval Reserve at Naval Air Station Corpus Christi on June 9, 1943 (just three days before his 19th birthday), which made him the youngest naval aviator to that date.

In September 1943, he was assigned to Torpedo Squadron 51 (VT-51) as the photographic officer. The following year, his squadron was based in USS San Jacinto as a member of Air Group 51, where his lanky physique earned him the nickname "Skin". During this time, the task force was victorious in one of the largest air battles of World War II: the Battle of the Philippine Sea.

After Bush's promotion to lieutenant (junior grade) on August 1, 1944, San Jacinto commenced operations against the Japanese in the Bonin Islands. Bush piloted one of four Grumman TBM Avengers of VT-51 that attacked the Japanese installations on Chichijima. His crew for the mission, which occurred on September 2, 1944, included Radioman Second Class John Delaney and Lt.(jg) William White. During their attack, the Avengers encountered intense anti-aircraft fire; Bush's aircraft was hit by flak and his engine caught fire. Despite the fire in his aircraft, Bush completed his attack and released bombs over his target, scoring several damaging hits. With his engine ablaze, Bush flew several miles from the island, where he and one other crew member of the TBM bailed out; the other man's parachute did not open. Bush waited for four hours in an inflated raft, while several fighters circled protectively overhead, until he was rescued by the submarine USS Finback, on lifeguard duty. For the next month, he remained in Finback and participated in the rescue of other aviators. Several of those shot down during the attack were executed, and their livers were eaten by their captors. A radio operator from the Japanese unit which shot down the Bush plane was American citizen Nobuaki Iwatake, a Japanese American who had settled in Japan six months before Pearl Harbor and was drafted into the Japanese Imperial Army in 1943. This experience shaped Bush profoundly, leading him to ask, "Why had I been spared and what did God have for me?"

In November 1944, Bush returned to San Jacinto and participated in operations in the Philippines until his squadron was replaced and sent home to the United States. Through 1944, he flew 58 combat missions for which he received the Distinguished Flying Cross, three Air Medals, and the Presidential Unit Citation awarded to San Jacinto. Bush was then reassigned to a training wing for torpedo bomber crews at Norfolk Navy Base, Virginia. His final assignment was to a new torpedo squadron, VT-153, based at Naval Air Station Grosse Ile, Michigan. Bush was honorably discharged from the U.S. Navy in September 1945, one month after the surrender of Japan.