Opened on Main Street in 1928, it was named in honor of the Kentuckian and United States statesman, Henry Clay.

[6] Seventy years later, the first four-year high school in Lexington opened on the corner of Walnut and Short streets.

On July 6, 1928, the board adopted the name Henry Clay High School, requested by the Daughters of the American Revolution.

[6] The demographic breakdown by race/ethnicity of the 2,058 students enrolled for the 2021–2022 school year was:[3] The Henry Clay Speech and Debate team is currently[when?]

In the 2012–2013 season, the Henry Clay men's lacrosse team posted an undefeated 18–0 record, defeating Lexington Catholic High School by a score of 10–4 to capture the Division 2 State Championship.