He played in Major League Baseball (MLB) from 2010 to 2019 for the New York Mets, Tampa Bay Rays, Atlanta Braves, and Kansas City Royals.

[4] Duda began the 2010 season continuing to play for the Double–A Binghamton Mets, and was promoted to the Triple–A Buffalo Bisons on June 14.

[6] On August 31, 2010, the Mets announced that Duda would be added to the major league roster as part of their September call-ups.

[5][7] Duda made his major league debut on September 1, against the Atlanta Braves, facing starting pitcher Tommy Hanson, whom he played against in high school.

[2][7] Duda had to leave the game in the eighth inning due to hamstring cramps, which he said came from dehydrating while on the plane from Buffalo to Atlanta.

[13] On August 8, 2011, batting in the cleanup spot for the first time in his major league career, Duda picked up his first major-league walk-off hit, with a two-run single off of Padres closer and former Mets reliever Heath Bell.

On April 7, 2012, Duda had his first multi-homer game, hitting two solo shots off the Atlanta Braves in a 4–2 Mets' victory.

[11] In October, Duda broke his right wrist while moving furniture at his home in South California, and had surgery on November 5.

[11] With Ike Davis still occupying first base, Duda played the majority of his defensive games in the corner outfield positions for the fourth consecutive season.

[10] On April 4, Mets manager Terry Collins announced that Duda would get the bulk of the playing time at first base over Ike Davis.

[20] On April 18, after a positional battle which lasted several seasons and a struggle with valley fever, Ike Davis was traded to the Pittsburgh Pirates for Zack Thornton and a player to be named later, later revealed to be Blake Taylor.

[21] On August 1, Duda hit his 20th home run of the season against the San Francisco Giants' pitcher Ryan Vogelsong.

[28] In the fourth game of the 2015 NLCS, Duda batted in five runs to help the Mets sweep the Chicago Cubs and advance to the 2015 World Series.

[30] Duda's errant throw to home in the 9th inning of Game 5 of the World Series with 2 outs and the Mets leading 2–1 allowed Eric Hosmer to score the tying run, and cost the Mets the game when the Kansas City Royals won in 12 innings, completing their World Series championship.

On April 3, Duda was the starting first baseman for Opening Day, going 1–3, logging one walk, one strikeout and hitting a three-run double in the bottom of the seventh off Eric O'Flaherty against the Atlanta Braves.

[34] On April 21, the Mets placed Duda on the 10-day disabled list, two days after he suffered a hyperextended left elbow in a collision at first base with Philadelphia Phillies baserunner César Hernández.

On July 27, 2017, the Mets traded Duda to the Tampa Bay Rays for minor league pitcher Drew Smith.

[41][42] On February 9, 2019, Duda signed a minor-league contract with the Minnesota Twins that included an invitation to spring training.