The B-25 can trace its lineage back to the mid-1930s development of the XB-21 (Model NA-39). Only one twin-engine XB-21 was built, but North American used experience gained for the company-financed NA-40 project. This aircraft was also a twin-engine design but had a tricycle landing gear rather than the tail-dragger configuration of the XB-21. Only one NA-40 was built, and it had several modifications done to test various features, including an engine change. The original Pratt & Whitney R-1830 engines were replaced by Wright R-2600s, which became standard on the B-25.

The NA-40B was initially submitted for evaluation as an attack bomber for export use by Great Britain and France, which had an immediate need for aircraft in the early stages of World War II. The aircraft lost to what would become the Douglas A-20 Havoc but gained new life when it was evaluated for use as a medium bomber even though the aircraft was destroyed in a crash on April 11, 1939.

The redesigned NA-40B was designated NA-62 by North American, and along with th e Martin B-26, was selected for production in 1939. 184 aircraft were ordered and were eventually delivered as 24 B-25s, 40 B-25As and 120 B-25Bs. The B-25 was so desperately needed, no experimental or service test (XB-25 or YB-25) aircraft were built. Changes to the basic design were incorporated into aircraft on the production line and post-production or depot modification centers. One significant change involved a design of the wing. The first nine B-25s were built with constant dihedral (angle) wings; however, stability problems forced a change that kept the dihedral angle on the inboard wing but nullified it on the outboard wing (0 angle). This gave the B-25 its distinctive "gull wing." Another change replaced smaller angled vertical stabilizers with larger less angled ones.

Before production ended, approximately 10,000 B-25s were built of all types, which included a reconnaissance (F-10) and Navy version (PBJ-1). The B-25 was also used by numerous foreign countries including Great Britain, which received more than 900 aircraft by war's end.