She is the author of Providence Island, 1630-1641: The Other Puritan Colony (1993), which won the Beveridge Prize of the American Historical Association. She also authored Roanoke, The Abandoned Colony (1984), and Settling With the Indians: The Meeting of English and Indian Cultures in America, 1580-1640 (1980).

Her edited books include America in European Consciousness (1995), Major Problems in American Colonial History (1993), and Captain John Smith: A Select Edition of His Writings (1988).

Her essay "Apathy and Death in Early Jamestown," published in the Journal of American History in 1979, won the Binkley-Stephenson Award of the Organization of American Historians. Professor Kupperman was the Times-Mirror Foundation Distinguished Fellow at the Huntington Library in 1995-96. She held a Mellon Faculty Fellowship at Harvard University in 1980-1981 and was a fellow of the National Humanities Center in 1984-1985. In 1988 she was a Rockefeller Foundation fellow at the Villa Serbelloni in Bellagio, Italy; and, in 1989, a National Endowment for the Humanities fellow at the John Carter Brown Library. She has chaired the Council of the Institute of Early American History and Culture and the editorial board of the William and Mary Quarterly.