On September 13, 1897, opening-day classes for 586 boys were held on the top floor of a grammar school on 13th Street in Manhattan. With enrollment rapidly increasing every year, students and staff moved in 1906 to their own new building at 59th and Tenth Avenue. Then in 1929 when an even larger building was needed, DeWitt Clinton High School traveled to its present campus location on Mosholu Parkway in The Bronx.

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Originally named Boys High School of Manhattan, the school was renamed in 1900 to honor New York City Mayor and New York State Governor DeWitt Clinton, who had begun the city's public school system in 1804. Clinton remained all boys until 1983. Today, the school is equally co-ed with classes, activities, and teams organized to provide a wonderful high school experience for every student.