The idea of establishing a collegiate school to raise educational standards in the Gold Coast was first mooted in 1865 but was not realized until 1876 when the Wesleyan High School was established in Cape Coast with donations from local businessmen and the support of the Methodist Missionary Society in London.

The school was established to train teachers and began with 17 pupils. It was originally planned to be sited in Accra because the British Government had, by 1870, decided to move the capital of the Gold Coast from Cape Coast to Accra. However, local agitation and the urgent need to put the idea into practice after eleven years of debate pressurised the government to allow the school to begin functioning, but on the understanding that it would later be moved to Accra, though no such move ever took place.

The founding name of Mfantsipim was Wesleyan High School and it was established on 3 April 1876. In 1905 a graduate of the school, [John Mensah Sarbah], founded a rival school named Mfantsipim; the name derives from "Mfantsefo-apem", literally meaning "thousands of Fantes " but actually meaning "the gathering of hosts of scholars for change" originally by the Fantes. In July of the same year, the two schools were merged under the control of the Methodist Church, keeping the name Mfantsipim. John Mensah-Sarbah, who came up with the name "Mfantsipim" stated at the opening of the school that its aim was "to train up God-fearing, respectable and intelligent lads."