Randall-MacIver began his career working with Flinders Petrie in Egypt, uncovering the mortuary temple of Senwosret III. He moved to America when he was appointed as Egyptology curator at the Penn museum in 1905. He initiated research into the relationship between Egypt and Nubia, uncovering some of the earliest evidence of ancient Nubian culture, dating back to 3100BCE. Between 1905 and 1906 Randall-MacIver conducted the first detailed study of Great Zimbabwe. The absence of any artefacts of non-African origin led him to conclude that the structure was built by local people. Earlier scholars had speculated that the structure had been built by Arab or Phoenician traders.
Randall-MacIver left Penn museum in 1911, becoming librarian of the American Geographical Society up to 1914, when he left to work as an intelligence officer in the First World War. In 1921 he moved to Italy to study Etruscan archaeology. He remained in Italy during World War Two, later assisting the US army to preserve historical monuments.