Designed for attack the Zero gave precedence to maneuverability and fire-power at the expense of protection - most had no self-sealing tanks or armor plate - thus many Zeros were lost too easily in combat. Nevertheless, many Allied pilots died trying to learn how to fight such an agile aircraft.

The correct combat tactic against Zeros was to remain out of range and fight on the dive and climb. By using speed and resisting the deadly error of trying to out-turn the Zero, eventually cannon could be brought to bear and a single burst of fire was usually enough.

When the US had learned the "secret" of the Zero new aircraft such as the Grumman Hellcat and Vought Corsair were introduced, planes that outperformed the Zero in every way but maneuverability. To correct for that shortcoming, US pilots simply had to remember the correct tactics. The result was that the Model 22s were swept from the skies in huge numbers, and the US Navy's 1:1 kill ratio suddenly jumped to better than 10:1. However Japanese development did not remain static - newer planes like the George were excellent fighters and a match for the later US models.

As the war progressed, the Zero, once the most feared fighter in the Pacific, became outclassed by new more powerful American fighters. Even so, it remained an important factor in the Pacific theater, for it was used for kamikaze, or suicide, missions that inflicted some of the most severe damage of the war on the U.S. Navy. Loaded with explosives and manned by pilots willing to lose their lives for their country, the Zero became a flying bomb aimed at American ships. The Zero was used in nearly 2,000 kamikaze attacks before Japan finally surrendered to bring down the curtain on the war in the Pacific.

The Zero fighter ranks with the Supermarine Spitfire, Vought Corsair and North American Mustang as one of the historic fighters of World War II.