Pietrosante was selected by the Detroit Lions in the first round, sixth overall pick, of the 1959 NFL Draft. As a rookie in 1959, he rushed for 134 yards against the Green Bay Packers on Thanksgiving Day, the best rushing total recorded by a Lion since Bob Hoernschemeyer rushed for 198 yards in 1950. After the game, Green Bay coach Vince Lombardi said, "That boy shall be a great one some day. He is very tough to bring down." He also led the NFL with an average of 5.9 rushing yards per carry and won the 1959 National Football League Rookie of the Year Award.