Lefkowitz earned her B.A. from Wellesley College in 1957 and received her Ph.D. in classical philology from Radcliffe College (now part of Harvard University) in 1961.

Lefkowitz has published on subjects including mythology, women in antiquity, Pindar, and fiction in ancient biography. She has come to the attention of a wider audience through her criticism of the claims of Afrocentrism, particularly in Not Out of Africa: How Afrocentrism Became an Excuse to Teach Myth As History, in which Lefkowitz laid out the scholarly case against the kind of black history found in Martin Bernal's The Afroasiatic Roots of Classical Civilization. In Black Athena Revisited (1996), which she edited with her Wellesley colleague, Guy MacLean Rogers, the ideas of Martin Bernal are further scrutinized. In 2008, Lefkowitz published History Lesson, an account of what she experienced as a result of questioning the veracity of Afrocentrism.

From 1982 until his death in 2009, Lefkowitz was married to Sir Hugh Lloyd-Jones, Regius Professor Emeritus of Greek at Oxford University.