Smith obtained an appointment at the Cairo School of Medicine in 1900 on the suggestion of his anthropologist friend Alexander Macalister. Smith became archaeological advisor to the archaeological survey of Nubia in the wake of plans to construct the Aswan Dam which threatened to drown numerous archaeological sites. Smith conducted investigations on the brains of Egyptian mummies. He was the first to non-destructively use x-rays to study mummies. Smith took a special interest in the pathologies indicated in ancient skeletal remains. He noted for instance that many Egyptian skulls had biparietal thinning which had been common in European aristocrats in the past. Smith hypothesized this was the result of wearing heavy wigs or headgear. From 1909 to 1919 he was Professor in anatomy in Manchester, 1919–1937 he held the chair of Anatomy at the University College London. He was elected President of the Anatomical Society of Great Britain and Ireland for 1924 to 1927. During World War I he took an interest in the neurology of shell shock, visiting military hospitals and serving on the British General Medical Council.