He first worked as an apprentice to Leonard Woolley at the archaeological site of Ur (1925–31), which was thought to be the capital of Mesopotamian civilization. (It was at the Ur site, in 1930, that he first met Agatha Christie.) In 1932, after a short time working at Nineveh with Reginald Campbell Thompson, Mallowan became a field director for a series of expeditions jointly run by the British Museum and the British School of Archaeology in Iraq. His excavations included the prehistoric village at Arpachiyah, and the sites at Chagar Bazar and Tell Brak in northern Syria. During the Second World War he served with the Royal Air Force Volunteer Reserve in North Africa, being based for part of 1943 at the ancient city of Sabratha. After the war, in 1947, he was appointed Professor of Western Asiatic Archaeology at the University of London, a position which he held until elected a fellow of All Souls College, Oxford in 1962. In 1947 he also became director of the British School of Archaeology in Iraq (1947-1961), and directed the resumption of its work at Nimrud (previously excavated by A. H. Layard), which he published in Nimrud and its Remains (2 volumes, 1966).
Mallowan gave an account of his work in Twenty-five Years of Mesopotamian Discovery (1956), and his wife Agatha Christie described his work in Syria in Come, Tell Me How You Live (1946).
Agatha Christie died in 1976, and the following year Mallowan married his long-standing mistress, Barbara Parker. She was an archaeologist who had been his epigraphist at Nimrud, and Secretary of the British School of Archaeology in Iraq.