The school was constructed in 1925 and 1926 and was designed by the prolific Denver architecture firm of Fisher and Fisher. South High was one of four high schools built in Denver in the 1920s to meet growing enrollment as the city grew “up and out.” Named for the quadrant of the city they served, all four are understood today to be significant for the architectural distinction they brought to the cityscape and for their contribution to Denver's aesthetic and civic values.

The building is an outstanding example of First Romanesque/Italian Renaissance Revival style architecture and is a testament to the City Beautiful movement imprint on Denver. The 1963 additions were designed by notable mid-twentieth century modernist architect Charles Gordon Lee. The building also features lively and whimsical sculptural friezes and other details on the exterior and the interior that are the work of Robert Garrison, as well as two interior murals by the muralist Allen Tupper True.