As part of the Smithsonian Institution, the National Air and Space Museum supports the Institution’s founding mission — "the increase and diffusion of knowledge" — and its vision, values, priorities, and Grand Challenges.

The National Air and Space Museum is under the direction of the Under Secretary for Science, one of three Under Secretaries who report to the Secretary of the Institution. When it created the Smithsonian Institution in 1846, Congress vested responsibility for its administration in a Board of Regents.

The National Air and Space Museum is led by a Museum Director, assisted by three Associate Directors. The Department of Management and Public Programs includes Finance and Administrative Management; Information Technology; Education; Visitor Services; Human Resources; Health and Safety; Exhibits Production; and Exhibits Design and Technologies. The Department of Collections and Curatorial Affairs consists of the research divisions of Aeronautics, Space History, and Earth and Planetary Studies, as well as Archives, Collections, Publications, Research Fellowships, and Web and New Media. The External Affairs Department is responsible for the offices of Advancement, Special Events, and Communications. Business activities, security, facilities management, and other central operations are managed through the Smithsonian Institution.

The Museum benefits from the support provided by the National Air and Space Museum Board, which consists of up to 32 distinguished members of the air and space community. There are no less than two regular meetings of the Board each year. Approximately 70 percent of the Museum's funding comes from federal appropriations. The remainder is primarily provided through private and corporate donations, and support from the National Air and Space Society, the National Aviation and Space Exploration Wall of Honor, and special events. Other important sources of revenue are the business activities managed by Smithsonian Enterprises, which include stores, restaurants, theaters, and attractions, as well as Smithsonian media and publications.