The son of Mark Antony de Wolfe Howe, Mark de Wolfe Howe graduated from Harvard College in 1928. After a brief period working for Paramount Pictures as an assistant director, Howe attended Harvard Law School, and upon his graduation clerked for retired Supreme Court justice Oliver Wendell Holmes Jr..
In 1937, Howe was appointed professor of law at the University of Buffalo Law School. After service in World War II, he joined the faculty of Harvard Law School, and was named Charles Warren Professor of American Legal History two years before his death.