Thomas Mark Harmon was born in Burbank, California, to football player and broadcaster Tom Harmon and actress Elyse Knox (née Kornbrath). Harmon played college football and found success as one of TV's hunkiest actors. While many of his roles have relied on good looks, Harmon was impressive as the suave doctor on St. Elsewhere (1982) who contracted AIDS.
His sisters are Kelly Harmon, the Tic-Tac model, and Kristin Harmon, a painter and ex-wife of musician Ricky Nelson. He is the uncle of musicians Matthew Nelson and Gunnar Nelson of the band Nelson, and actress Tracy Nelson. In 1987, Harmon and his wife, actress Pam Dawber, sued his sister Kristin Harmon, for custody of her youngest son, Sam.