Dan Duquette's career in Major League Baseball is characterized by his roles as a general manager and executive, where he played a substantial part in shaping several teams. His journey in baseball management began with the Montreal Expos, where he served as the general manager from 1991 to 1994. During his tenure, Duquette was instrumental in assembling a talented roster that included players like Pedro Martinez, Larry Walker, and Moises Alou. Under his guidance, the Expos became a competitive team in the National League, and in 1994, they had the best record in baseball before the season was cut short by a strike.

Following his time with the Expos, Duquette moved on to the Boston Red Sox, where he served as general manager from 1994 to 2002. In Boston, he was responsible for acquiring several key players, including Pedro Martinez, who would go on to become one of the most dominant pitchers in the game. Duquette also played a role in bringing Manny Ramirez to the Red Sox, further strengthening the team's lineup. His efforts helped lay the groundwork for the Red Sox's future success, although he left the organization before they won the World Series in 2004.

After a period away from Major League Baseball, Duquette returned to the sport in 2011 when he was hired as the executive vice president of baseball operations for the Baltimore Orioles. His leadership helped revitalize the Orioles, who had struggled for many years. Duquette's strategic acquisitions and focus on building a strong farm system contributed to the Orioles' return to competitiveness. Under his management, the team made the playoffs in 2012, 2014, and 2016, including an appearance in the American League Championship Series in 2014.