Mfantsiman Girls' Secondary School was formerly known as Saltpond Girls' Secondary School. The name was changed to Mfantsiman when the District of Saltpond became the District of Mfantsiman. The school was founded by the late Osagyefo Dr. Kwame Nkrumah, President of the First Republic of Ghana as a special gesture of appreciation to the people of Saltpond for the part the town played in the political history of the country. His aim was to empower girls in the area and in addition establish a Polytechnic for girls.

A group of prominent persons were selected to choose the site for the School, and this team were made up as follows: Mr. Kojo Botsio, Minister of Education, Mr. Kofi Baako, Member of Parliament of Saltpond, Mr. George Padmore, West Indian Pan-Africanist, Dr. Hastins Banda, President of the Republic of Malawi, and Mr. S.E. Arthur, Member of the School Board of Governors. The area where the school is established used to be called Kuntupow. Constructional work of the school thus began in 1958 on a land size measuring 430.10 acres. Part of the first phase consisted of the Administration Block, Classroom Block, Science Block, Dining Hall, one teacher's bungalow and the headmistress's bungalow were completed in September 1960.