The school was founded by the wife of the 2nd Methodist Missionary to the Gold Coast, Mrs. Harriet Wrigley in 1836 with 25 girls. Her aim was to give the girls basic training in housekeeping and catechism. Subjects taught included writing, reading, sewing and religious education. Classes were held at the Manse, in the Standfast Hall near the Victoria Park in Cape Coast.
Values such as fortitude, integrity and truthfulness soon became the hallmarks of the products of the school. Their high academic ability encouraged the Methodist church to agree to the provision of higher education for girls. Consequently, in 1884, Rev. W. M. Cannell who was then the Headmaster of Mfantsipim School started the Secondary section with 20 girls.
In 1951, the Secondary School section was separated definitely from the primary when Miss Olive Compton moved the Secondary division of the school to its present site at Kakumdo. The firm establishment of the high School is attributed to Miss Compton who conceptualized the school as H.M.S Excellence (A Ship) and had the school designed architecturally as such.
With time, the glamour of the high school eclipsed the primary section which has not regained its former glory till today.
Subsequent headmistress; Miss Clarice Garnett, the last of the missionaries saw to the establishment of the sixth form for science (the arts had already been established by Miss Compton). Miss Clarice Garnett handed over to the first African headmistress of the school, Mrs. Rosina Acheampong, who had to work hard to prove to the whole world that the black woman was also capable of running the school of excellence. Despite the challenges that the 1987 Education Reform posed with the resultant structural change that made the secondary course 3 years instead of the 7 years, Mrs. Rosina Acheampong was able to maintain discipline and such high academic standards that the school became the most desired by girls in the country. She was succeeded in 1997 by Mrs. Nancy Thompson, another old girl of the school. She increased the intake from 800 to about 1200 and expanded the infrastructure whilst maintaining the high academic standards.
In 2003, she retired and Mrs. Betty Djokoto, another old girl of the 1975 year group, who had been Assistant Headmistress for 7 years in the school, became the Headmistress. During her time, admission to the school is through the Computerized School Selection and Placement System (CSSPS). The implications of this new system of admissions for the school coupled with current low morale of teachers are challenges she must work hard to overcome if standards are to be maintained.
However, with the current successes that the school has chalked up by producing he Best General Art Student, in he 2005 Secondary School certificate Examination (SSCE) and the 1st and 2nd Overall Best Candidates, as well as the Best Science Student and the Best Buisness Student in the West African Secondary School Certificate Examination (WASSCE) 2006, it is obvious that she is determined to continue the tradition of excellence for which the school has been known for decades.