Sanford High began offering high school level classes in 1887, and during the 20th century was the first school in the State of Maine to earn state accreditation and New England accreditation, a status which has since been continuous.

Growth in enrollment and programming eventually required up to twenty-four classrooms in portable structures around the main building.

A new $103,000,000 campus opened on October 10, 2018, at 100 Alumni Boulevard with expanded programs in the regional technical center, integrated academic programs, and state-of-the-art academic, technical, and performing arts facilities as well as much enhanced athletic fields and indoor facilities along with a competition turf field 2,000-seat stadium, dedicated "Alumni Stadium" at its first home football game on August 31, 2018.

The boys' soccer team won the 1999 Western Maine Class "A" Championship.

Other teams have won state championships in Wrestling, Field Hockey, and Girls' Track.