After teaching as a Lecturer in History and Literature at Harvard for two years, he took a position at the University of Kansas in 1989.
In 2001, Mancall took a position at the University of Southern California, where he helped to create the USC-Huntington Early Modern Studies Institute in 2003, becoming its first director.
He has served on the editorial board of several journals, and from 2007 to 2009 he was Associate Vice Provost for Research Advancement at the University of Southern California.
During the 2019-2020 academic year, Mancall served as the Harold Vyvyan Harmsworth Professor of American History at Oxford University.
His newest book, The Trials of Thomas Morton: An Anglican Lawyer, His Puritan Foes, and the Battle for a New England, was published by Yale University Press in 2019.