He played in Major League Baseball (MLB) for the Cincinnati Reds, Toronto Blue Jays, Cleveland Indians, Seattle Mariners, New York Yankees, and Chicago White Sox.

[1] The Texas Rangers selected Encarnación in the ninth round of the 2000 Major League Baseball draft, and he signed with them.

On June 15, 2001, the Rangers traded him and Rubén Mateo to the Cincinnati Reds in exchange for pitcher Rob Bell.

He was frequently benched in favor of Ryan Freel, which gave Josh Hamilton, who was attempting to resurrect his career after it was derailed by addiction to drugs and alcohol, more starts in center field.

[2] Encarnación, along with right-handed pitchers Josh Roenicke and Zach Stewart, was traded to the Toronto Blue Jays for Scott Rolen on July 31, 2009.

[2] During the offseason, Encarnación suffered first and second-degree burns to the forehead and the right side of his face when a rocket firecracker hit him in the jaw and exploded near his mouth.

[10] Encarnación was eventually assigned to Triple-A Las Vegas on June 23, 2010, but was later called up to the Blue Jays again on July 2, 2010, after a struggling performance by Encarnacion's replacement, Jarrett Hoffpauir.

In a game against the Boston Red Sox on September 7, 2011, Encarnacion set a new career record for doubles in a single season with 34.

On September 22, Encarnacion hit a walk-off home run off the Rogers Sportsnet One sign in the 12th inning against Angels rookie Garrett Richards.

[13] In a game against the Seattle Mariners on April 28, 2012, Encarnación hit his fourth career grand slam in the 8th inning leading the Blue Jays to a 7–0 win.

[14] His grand slam marked the first time that Encarnación held his arm out in his trademark "chicken-wing" fashion while rounding the bases.

[17] In an inter-league game against the Milwaukee Brewers on June 19, Encarnación hit the last of three straight solo home runs by the Blue Jays, following Colby Rasmus and José Bautista, the first time in the 2012 season that the Jays went back-to-back-to-back with home runs, and only the sixth time in franchise history.

[21] Encarnación was unanimously named by the Baseball Writers' Association of America (BBWAA) as the Blue Jays Player of the Year on November 28, 2012.

[22] On May 23, 2013, Encarnación hit his fifth career grand slam to give the Blue Jays an 8–3 lead over the Baltimore Orioles.

On September 2, he reached 100 RBIs for the second consecutive season on a two-run home run against Brandon McCarthy of the Arizona Diamondbacks.

[33] The following day, Encarnación tied the team record for home runs in any month of the season, when he hit his 14th to help the Blue Jays extend their winning streak to 8 games.

His 6 RBIs were a key contribution in helping the Blue Jays to their second-largest comeback victory in franchise history, being down 8–0 after the second inning and going on to win 14–9.

[39] He joined fellow Blue Jay José Bautista on the list of active players to hold this distinction.

[47] On September 2, Encarnación won the American League Player of the Month award for the second time in his career, after batting .407 with 11 home runs and 35 RBIs in August.

[50] Prior to 2016 spring training, Encarnación set an Opening Day deadline to negotiate a contract extension with the Blue Jays.

[52] Encarnación hit his fourth walk-off home run as a Blue Jay on June 10, defeating the Baltimore Orioles 4–3 in the tenth inning.

In doing so, he became the Blue Jays all-time leader in walk-off home runs as well as the eighth player in franchise history to reach 600 RBI.

[53] In the first inning of a game on July 1, Encarnación was ejected by home plate umpire Vic Carapazza for arguing balls and strikes.

[58] In the eleventh inning of the 2016 Wild Card game, Encarnación hit a walk-off, three-run home run to give the Blue Jays a 5–2 victory over the Baltimore Orioles and send them to the American League Division Series to face the Texas Rangers.

On June 15, 2019, the Mariners traded Encarnación to the New York Yankees in exchange for minor league pitcher Juan Then and cash considerations.

[68] On August 3, Encarnación was hit by a pitch; he left the game with a fractured right wrist, and was placed on the 10-day injured list later that day.

On October 31, 2019, the New York Yankees announced they would not be exercising their club option for Encarnación for 2020, allowing him to enter the 2019-2020 free agent market.

[70] On July 24, 2020, he was the starting designated hitter, making his White Sox debut on Opening Day against the Minnesota Twins.

[2] On February 24, 2023, Encarnación joined the coaching staff of the Toronto Blue Jays, helping to assist the club during spring training.