It was built beginning in 1930, to house the expanded offices of the United States Department of Agriculture (USDA).

[2] The building's design is credited to Louis A. Simon of the Federal Office of the Supervising Architect.

The C Street and Independence Avenue elevations, which are not visible from the National Mall, used brick as the primary material, with limestone and terra cotta detailing.

Elsewhere, relief panels between windows feature depictions of animals native to the United States by sculptor Edwin Morris.

[4] Since the relocation of laboratory space to the Beltsville Agricultural Research Center, the South Building has been occupied exclusively by offices.