Clarke received his Ph.D. in the history of art from Yale University in 1973. He taught at Yale University before coming to the University of Texas at Austin in 1980. He has published eight books and more than 80 articles and chapters on ancient Roman art, architecture and visual culture, as well as critical essays on contemporary art, theory, and the digital humanities.

Clarke currently co-directs the Oplontis Project, a collaboration among 46 scholars worldwide aimed at publishing two contiguous UNESCO World Heritage sites located three miles from Pompeii, both buried by the eruption of Vesuvius in 79 CE. Villa A ('of Poppaea') was an enormous ancient Roman luxury villa, whereas Villa B was a commercial complex devoted to the wine industry. Clarke has overseen sixteen seasons of excavation and study, funded by the National Endowment for the Humanities, the Oplontis Project in the Department of Art and Art History, and by anonymous donors. He co-edited two volumes on Villa A in a series of Open Access electronic books published by the University of Michigan Press for the American Council of Learned Societies. Fully-navigable 3D models of the Villas will provide a portal into the Project's extensive databases.