[1][2] In 2015, he was named the Sporting News Executive of the Year after the Blue Jays advanced to the playoffs for the first time since 1993, reaching the American League Championship Series (ALCS).

[11] He began his tenure as the general manager by playing a major role in one of the biggest trades in Blue Jays history, "The Doc Deal".

In the deal, Anthopoulos traded Roy Halladay to the Philadelphia Phillies for Kyle Drabek, Michael Taylor, and Travis d'Arnaud.

[13] The Jays' first season with Anthopoulos at the helm resulted in an 85–77 record, good for fourth place in the American League (AL) East division.

[15] He then sent Napoli to the Texas Rangers for pitcher Frank Francisco,[16] and later traded Rivera to the Los Angeles Dodgers for a player to be named later or cash considerations.

[17] In July 2011, Anthopoulos made two successive trades to acquire center fielder Colby Rasmus from the St. Louis Cardinals.

In the first, the Blue Jays traded pitching prospect Zach Stewart and reliever Jason Frasor to the Chicago White Sox for starting pitcher Edwin Jackson and infielder Mark Teahen.

[19] Before the 2012 Major League Baseball season, Anthopoulos was known to make trades in order to acquire supplemental draft picks.

[20] The Blue Jays gained a supplemental first-round draft pick when Olivo signed with the Seattle Mariners, taking Dwight Smith, Jr.[21] In November 2012, Anthopolous completed a blockbuster deal with the Miami Marlins, acquiring shortstop Jose Reyes, pitchers Mark Buehrle and Josh Johnson, catcher John Buck, and infielder/outfielder Emilio Bonifacio in exchange for shortstop Yunel Escobar, pitcher Henderson Alvarez, catcher Jeff Mathis and four minor-league prospects.

[27] In July 2015, he acquired Troy Tulowitzki and LaTroy Hawkins from the Colorado Rockies in exchange for Jose Reyes, Jeff Hoffman, and Miguel Castro.

[28] On July 30, he acquired star left-handed pitcher David Price from the Detroit Tigers in exchange for Daniel Norris, Matt Boyd, and Jairo Labourt.

[32] The Blue Jays, who had a 50–51 record on July 28, won 43 of their final 61 games to overtake the New York Yankees and win the AL East division crown for their first playoff appearance in 22 seasons.

[41] On November 13, 2017, Anthopoulos was hired as the executive vice president and general manager of the Atlanta Braves after agreeing on a four-year contract.

[49] In March of 2022, Anthopoulos completed a blockbuster trade acquiring first baseman Matt Olson from the Oakland Athletics in exchange for four prospects: outfielder Cristian Pache, catcher Shea Langeliers, and right-handers Ryan Cusick and Joey Estes.

[59][60] Anthopoulos served as an advance scout for the Greek National Baseball Team for the 2004 Summer Olympics; which finished in 7th place.