Work on the school began in 1868 and it opened in 1873 with 46 boys, under the direction of Edward Clarke Lowe, provost of the Midland district of the Woodard Corporation.

[2] The school's chapel was built in 1879–87 by Carpenter and Benjamin Ingelow in a late 13th-century Gothic style; it consists of a four-bay nave with a polygonal apse.

A Royal and Ancient-accredited nine-hole golf course was opened in 1992, a new sports hall in 2000 and the schoolroom was completely refurbished as a modern theatre in 2003.

A further classroom block and the new sports pavilion and complex were completed in 2012, followed by a new library in 2014 and a university-style extension to girls boarding accommodation.

Denstone College is noted for carrying out the most extensive scientific exploration of Inaccessible Island, an extinct volcano in the South Atlantic.

The exterior of the school was used as a location for the convent where Novice Joyce Fuddle lived for episode 4 of the 1985 BBC comedy series Happy Families.