Hentgen was offered a baseball scholarship to Western Michigan University, but signed with the Toronto Blue Jays instead after being drafted in the 5th round of the 1986 free-agent draft. He made his debut in 1991 and played a large part in their World Series championships in 1992 and 1993. His best year, however, came in 1996 when he went 20-10 with a 3.22 ERA and 177 strikeouts to win the American League Cy Young Award, barely beating New York Yankees pitcher Andy Pettitte.
Traded to the St. Louis Cardinals in 1999, he then played for the Baltimore Orioles from 2001 to 2003. Hentgen had Tommy John surgery in 2001 (a procedure in which a tendon is extracted from a pitcher's non-throwing arm and used to replace the torn ligament on his pitching arm, threading the tendon through holes drilled into the bone above and below the elbow. It is named after former Los Angeles Dodgers pitcher Tommy John, for whom the procedure was devised. It is the same operation performed on the Atlanta Braves' John Smoltz.)
On July 24, 2004, Hentgen announced his retirement from baseball. The right-hander left with his name all over the Blue Jays' team record book, ranking in the top five in wins (107), starts (238), innings pitched (1,636) and winning percentage (.557). Overall, the three-time All-Star spent 14 seasons in the majors, going 131-112 with 34 complete games, 1290 strikeouts and a 4.32 ERA.
Hentgen and his wife, Darlene, have three girls.