On January 25, 1939, the USAAC announced a competition for a medium bomber design, but instead of waiting for the prototypes, the Army awarded production contracts to North American for the B-25 and Martin for the B-26. The B-25 served in every theater of World War II and was made in larger quantities than any other American twin-engine combat airplane.

B-25s entered service in 1941. On April 18, 1942, Lt. Col. James H. "Jimmy" Doolittle led the Doolittle Raid, in which 16 B-25B crews took off from the aircraft carrier USS Hornet (CV-8) and bombed Tokyo and other targets, the first time US aircraft had bombed Japan.

The original design had shoulder-mounted wings and a crew of three in a narrow fuselage. The USAAC then decided its new bomber would need a much larger payload -- double the original specifications. North American designers dropped the wing to the aircraft's mid-section, and widened the fuselage so the pilot and co-pilot could sit side-by-side. They also improved the cockpit. The USAAC ordered 140 aircraft of the new design right off the drawing board.

There were at least six major variants of the Mitchell, from the initial B-25A and B-25B, with two power-operated two-gun turrets, to the autopilot-equipped B-25C, and the B-25G with 75mm cannon for use on anti-shipping missions. The British designated the B-25Bs as the Mitchell I, the B-25C and B-25Ds as the Mitchell II, and their B-25Js, with 12 heavy machineguns, as the Mitchell III. The US Navy and Marine Corps designated their hard-nosed B-25Js as the PBJ-1J. In the end, the B-25 became the most widely used American medium bomber of WWII. 11,733 were built.

After the war, many B-25s were used as training aircraft. Between 1951 and 1954, 157 Mitchells were converted as flying classrooms for teaching the Hughes E-1 and E-5 fire control radar. They were also used as staff transport, utility, and navigator-trainer aircraft. The last B-25, a VIP transport, was retired from the USAF on May 21, 1960.