Pat Hentgen signed with the Toronto Blue Jays after being drafted in the 5th round of the 1986 Major League Baseball draft. He made his debut in 1991, and played a large part in the Blue Jays' World Series championship in 1993, winning 19 games in the regular season. 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. Hentgen was an American League All-Star in 1993, 1994, and 1997.
Hentgen was traded to the St. Louis Cardinals in 1999 and played for the Baltimore Orioles from 2001 to 2003. He had Tommy John surgery in August 2001 and returned on November 18, 2003 to the Blue Jays.
Hentgen was noted for his success in challenging hitters directly, mostly throwing his fastball for strikes to get ahead early in the count. This would set up his curveball or high fastball to strike out the batter.
After retiring Hentgen rejoined the Toronto Blue Jays under new manager John Farrell as their new bullpen coach for the 2011 season. It was Hentgen's first coaching assignment. In November 2011 he was given the title of Special Assistant to the Organization. On December 10, 2012, Hentgen was again appointed as the Blue Jays bullpen coach before eventually continuing his work with the Blue Jays as a special assistant to the organization to date.
In 2016, Hentgen was inducted into the Canadian Baseball Hall of Fame.