[3] The Board of Education purchased the property and building from the Institute for $250, naming it Union Free School No.

[2] By 1921, the original red brick building had been condemned by the State Department of Education as antiquated and unsanitary.

The current building on Main Street was constructed for an approved cost of $2.5 million,[2] and opened as Williamsville Junior-Senior High School on September 11, 1950, serving grades 7-12 and was dedicated on April 15, 1951.

[5] The building was designed by acclaimed local architect Duane Lyman, who was known as the dean of Western New York architecture.

[6] The building was added to the National Register of Historic Places (as "Williamsville Junior and Senior High School") in 2008.

[7][8] Williamsville South has long been an active participant in the Advanced Placement program.

[11] In 1994, the football team advanced to the New York State championship game (Class B), but was defeated by one point.