Whitt made his MLB debut for the Boston Red Sox in 1976. For eight consecutive seasons from 1982 to 1989, he reached double figures in home runs and 100 hits in each of five consecutive seasons from 1985 to 1989. He was selected as an All-Star in 1985. As manager for the Canadian national team, his competitions include the 2004 Summer Olympics, four World Baseball Classic (WBC) tournaments, and the Pan Am Games, where they won two gold medals in 2011 and 2015.
Whitt was selected in the 15th round of the 1972 amateur draft by the Boston Red Sox, and he made his major league debut on September 12, 1976, pinch hitting for Carlton Fisk in the seventh inning, grounding out. He finished the game as the Red Sox catcher, as Boston defeated the Cleveland Indians 11–3. Whitt recorded his first career hit on September 21, hitting a home run off of Jim Colborn of the Milwaukee Brewers in a 3–1 loss. He appeared in eight games with Boston, batting .222 with 1 HR and 3 RBI. With his path to the majors blocked by future Hall-of-Famer Carlton Fisk, he was left unprotected during the expansion draft held after the 1976 season and selected by the Blue Jays.
Whitt saw very little playing time with the Blue Jays in 1977, as in 23 games, he hit .171 with 0 HR and 6 RBI. In 1978, he saw even less time with Toronto, playing in just two games, going hitless in four at-bats. In 1979, Whitt spent the entire season with the Syracuse Chiefs, the Blue Jays AAA affiliate in the International League. Whitt speculated in his autobiography that Blue Jays manager Roy Hartsfield had a low opinion of his potential, as most of the catching duties went to Alan Ashby and Rick Cerone. With Hartsfield's departure prior to the 1980 season, new manager Bobby Mattick expanded Whitt's role as a player, and Whitt remained with the club for the next ten years.
In 1980, Whitt became the Blue Jays starting catcher, as he appeared in 106 games, hitting .237 with 6 HR and 34 RBI. He saw his numbers slip in 1981, as Whitt hit .236 with 1 HR and 16 RBI in 74 games during the strike-shortened season. On May 15 of the latter year, his fly ball was caught by Cleveland Indian outfielder Rick Manning for the final out of Len Barker's perfect game.
Whitt broke out offensively in 1982, as in 105 games, he hit .261 with 11 HR and 42 RBI for the Blue Jays. His 11 home runs ranked third on the team.
In 1985, Whitt was named to the 1985 Major League Baseball All-Star Game. He appeared in the game in the sixth inning as a defensive replacement for Carlton Fisk and caught teammate Dave Stieb. Whitt also caught in the seventh inning for Donnie Moore of the California Angels before Gary Ward of the Texas Rangers pinch hit for Whitt in the eighth inning. During the season, Whitt hit .245 with 19 HR and 64 RBI, as he helped the Blue Jays make the playoffs for the first time in team history. In the 1985 ALCS against the Kansas City Royals, Whitt appeared in all seven games, hitting .190 with 0 HR and 2 RBI as the Blue Jays lost the series.
On September 14, 1987, Whitt hit three home runs in a game against the Baltimore Orioles, helping the Blue Jays hit a major league record ten home runs in the game. Toronto defeated the Orioles 18–3. Whitt would have the best season of his career in 1987, as he hit .269 with 19 HR and 75 RBI in 135 games.
In 1989, Whitt played in 129 games, hitting .262, while getting 11 HR, his lowest total in a season since 1982, and his 53 RBI were the lowest total since 1984. In the playoffs, Whitt played in all five games against the Oakland Athletics in the 1989 ALCS, batting .125 with 1 HR and 3 RBI, as the Blue Jays lost the series.
To make room for young catchers Pat Borders and Greg Myers on the major league roster, on December 17, 1989, the Blue Jays traded Whitt and Kevin Batiste to the Atlanta Braves for Ricky Trlicek. Whitt was the last player from the expansion 1977 team to play for the Blue Jays.
Whitt parlayed his popularity into the publication of an autobiography, "Catch: A Major League Life", providing an insider's glimpse into both the 1988 season and his early days coming up through the minors. The book includes adventures such as entering bowling tournaments to win money for food. The book caused a stir upon publishing due to Whitt's controversial labeling of umpire Joe Brinkman as "incompetent." Due to his longevity as well as his production, he is widely regarded as the Blue Jays' greatest catcher of all-time.
Whitt joined the Atlanta Braves for the 1990 season, and had a very disappointing season, as he hit .172 with 2 HR and 10 RBI in 67 games. On October 15, the Braves released Whitt.
On April 7, 1991, Whitt returned to the American League, signing with the Baltimore Orioles. In 35 games, Whitt hit .242 with 0 HR and 3 RBI. On July 5, the Orioles released Whitt.
Whitt appeared in 1328 games over his career, 1218 of them with the Blue Jays. In his career, he recorded 938 hits, and had a batting average of .249 with 134 HR and 534 RBI. In 12 career playoff games, Whitt hit .162 with one home run and five RBI.
Whitt was inducted into the Ontario Sports Hall of Fame in 1997.
On June 20, 2009, it was announced that Whitt, along with former major league right fielder Larry Walker, were inducted into the Canadian Baseball Hall of Fame.
Whitt remained active as an ambassador of Canadian baseball following his major league career. In the 2004 Summer Olympics in Athens, he guided the Canadian team to a fourth-place finish in the baseball tournament. Whitt also managed the Canadian national baseball team to a third-place finish in Pool B at the 2006 World Baseball Classic.
Whitt also served as both the Blue Jays' bench coach and first base coach starting in 2005, and was rumoured to be a potential replacement for then-incumbent manager John Gibbons until Gibbons and several coaches were fired midway through the 2008 season. He was the manager of the Clearwater Threshers in the Philadelphia Phillies' minor league system. Whitt continues to be a roaming instructor in the Phillies' organization.
Whitt has managed Team Canada in following World Baseball Classics, World Baseball Cup, and the Pan Am Games. In the 2011 Pan Am Games in Guadalajara, Mexico, Canada won that tournament's gold medal. and a bronze medal in the IBAF World Baseball Cup.