McCall Smith was born in what is now Zimbabwe and was educated there and in Scotland. He became a law professor in Scotland, and it was in this role that he first returned to Africa to work in Botswana, where he helped to set up a new law school at the University of Botswana. For many years he was Professor of Medical Law at the University of Edinburgh, and has been a visiting professor at a number of other universities elsewhere, including ones in Italy and the United States. He is now a Professor Emeritus at the University of Edinburgh.

In addition to his university work, McCall Smith was for four years the vice-chairman of the Human Genetics Commission of the UK, the chairman of the British Medical Journal Ethics Committee, and a member of the International Bioethics Commission of UNESCO. He is the recipient of numerous awards, including The Crime Writers' Association's Dagger in the Library Award, the United Kingdom's Author of The Year Award in 2004 and Sweden's Martin Beck Award. In 2007 he was made a CBE for his services to literature in the Queen's New Year's Honor List. He holds honorary doctorates from 10 universities, most recently from Southern Methodist University, Dallas.