Together with its branch museum, the Renwick Gallery, SAAM holds one of the world's largest and most inclusive collections of art, from the colonial period to the present, made in the United States.

It maintains seven online research databases with more than 500,000 records, including the Inventories of American Painting and Sculpture that document more than 400,000 artworks in public and private collections worldwide.

[6] In its early years, however, little effort was put into developing the art collection, as Smithsonian Secretary Joseph Henry preferred to focus on scientific research.

[16] In 1924, architect Charles A. Platt drew up preliminary plans for a National Gallery of Art to be built on the block next to the Natural History Museum.

[21] In 1958, Congress finally granted the NCFA a home, the Old Patent Office Building, which was about to be vacated by the U.S. Civil Service Commission.

[26] The museum's relocation came at an unfortunate time, as the neighborhood had been devastated a month earlier by the Martin Luther King assassination riots.

[28] This would remain a factor until the late 1990s, when the work of the Pennsylvania Avenue Development Corporation and the opening of the MCI Center (now Capital One Arena) across the street from the museum sparked a revitalization of the neighborhood.

[29] The NCFA gained a new branch in 1972, opening the Renwick Gallery, dedicated to design and crafts, in a historic building near the White House.

[37] Many of the building's exceptional architectural features were restored: porticos modeled after the Parthenon in Athens, a curving double staircase, colonnades, vaulted galleries, large windows, and skylights as long as a city block.

[42] The museum and the National Portrait Gallery reopened their combined building, renamed as the Donald W. Reynolds Center for American Art and Portraiture, on July 1, 2006.

[38][44] Also under the auspices of the Smithsonian American Art Museum, the Renwick Gallery is a smaller, historic building on Pennsylvania Avenue across the street from the White House.

Among the significant artists represented in its collection are Nam June Paik, Jenny Holzer, David Hockney, Richard Hunt, Georgia O'Keeffe, Ching Ho Cheng, John Singer Sargent, Albert Pinkham Ryder, Albert Bierstadt, Frances Farrand Dodge, Edmonia Lewis, Thomas Moran, James Gill, Edward Hopper, John William "Uncle Jack" Dey, Karen LaMonte[48] and Winslow Homer.

[38][54][55][56] It presents more than 3,300 objects in 64 secure glass cases, which quadruples the number of artworks from the permanent collection on public view.

[51][38] The purpose of open storage is to allow patrons to view various niche art that is usually not part of a main exhibition or gala special.

[54] The Luce Foundation Center features paintings densely hung on screens; sculptures; crafts and objects by folk and self-taught artists arranged on shelves.

During the 2000s renovation, a "series of exhibitions of more than 1,000 major artworks from American Art's permanent collection traveled to 105 venues across the United States," which were "seen by more than 2.5 million visitors".

[61][81][82] In 2008, the American Art Museum hosted an alternate reality game, called Ghosts of a Chance, which was created by City Mystery.