Lepore earned a B.A. in English at Tufts University in 1987, an M.A. in history at University of Michigan in 1990, and a Ph.D. in American Studies from Yale University in 1995, where she specialized in the history of early America.

Before Harvard, Lepore taught at the University of California-San Diego and at Boston University.

In addition to her several books of history, in 2008 Lepore published a novel. She wrote it with Jane Kamensky, a professor at Brandeis University. Blindspot: a Novel (2008), features a rogue Scottish artist who has arrived in late 18th-century Boston as the American Revolution is on the verge of erupting. Another character is his young apprentice, an artistically talented girl who disguises herself as a boy to gain social freedoms.