A medical doctor by profession, Karefa-Smart was one of the founding fathers of the Sierra Leone People's Party (SLPP) in 1951.
After the death of Prime Minister Milton Margai in 1964, Karefa-Smart challenged Albert Margai for the SLPP leadership position, but he was unsuccessful, as Albert won the SLPP leadership and succeeded his brother as Sierra Leone's Prime Minister.
From there, he returned to Geneva, then migrated to the USA to pursue his career in university teaching, research and public speaking.
In 1996, Karefa-Smart returned to Sierra Leone's politics as the founder of the newly formed United National People's Party (UNPP).
From Otterbein, he went to McGill University in Montreal, where he received his MD and CM in 1944 and Diploma in Tropical Medicine in 1945.
In late July 2010, the Sierra Leonean government flew him back to Freetown, where he died on 26 August 2010.