The University’s earliest connection with Sierra Leone was through medical graduate Thomas Masterman Winterbottom (MD 1792), who, upon graduation, was appointed physician to the then colony of Sierra Leone, where he worked for seven years. His appointment coincided with the founding of Sierra Leone’s capital city Freetown by the Sierra Leone Company as a permanent settlement for former slaves and colonists of African descent from the Atlantic and Caribbean regions of the British Empire such as Nova Scotia and Jamaica. Winterbottom published his experiences and observations in An account of the native Africans in the neighbourhood of Sierra Leone (1803), and identified African sleeping sickness, whose diagnostic characteristic is known today as Winterbottom's sign.

In 1808 Sierra Leone became a British colony, and nineteenth-century missionaries demonstrated the new colony’s interest in spreading their religion and culture, including abolitionist ideas, throughout the region. Fourah Bay College, the oldest university in West Africa, was established in 1827 by the Church Missionary Society. The missionary society appointed a linguist, William Cooper Thompson, who also participated in a failed expedition into Timbo in neighbouring Guinea to establish communication links.

From 1885 to 1965, fifteen students born in Sierra Leone enrolled at the University. The majority were born in Freetown and came predominantly to study Medicine. It was also the Church Missionary Society that brought these first Sierra Leone-born students to the University following their attendance at Fourah Bay College. The first Sierra Leonean graduate was Frank Bright Marke. Born at Freetown, he graduated MB ChB 1933 and was closely followed by Taiwo Arthur Samuel Leighton-Decker, born at Murray Town, who graduated MB ChB in 1936.

During the Second World War, Zoology lecturer James Duncan Robertson continued the tradition of medical links between the countries, and the University’s long history of Malaria research, when he undertook research in Sierra Leone into the Plasmodium found within Anopheles mosquitoes, responsible for spreading malaria, while serving in the Royal Army Medical Corps in West Africa. Robertson’s extensive collection of specimens of mosquitoes from Sierra Leone is preserved by The Hunterian Museum.

With Sierra Leone’s Independence in 1961, students continued to attend the University to study Medicine, returning home to Sierra Leone to practice.