Minor leagues in 2007 Santana signed with the Los Angeles Dodgers in
2005. He began his professional
baseball career with the
Gulf Coast Dodgers, the rookie-level
minor league affiliate. He played 32 games in 2005 and
batted .295. He played primarily at
third base, while also appearing at
catcher,
second base, in
left field, and in
right field. On July 26, 2008, the Dodgers traded Santana and pitcher
Jon Meloan to the
Cleveland Indians for third baseman
Casey Blake. Santana appeared in 130 games combined in 2008 with the
Akron Aeros,
Inland Empire 66ers of San Bernardino, and
Kinston Indians during the 2008 season, with the majority at San Bernardino and Kinston at the
Class A-Advanced level, and played primarily catcher. On offense, he hit .326, amassed .431
on-base percentage (OBP), .568
slugging percentage (SLG), .999
on-base plus slugging (OPS), 125
runs scored, 21
home runs, collected 117
runs batted in (RBI), 89
bases on balls (BB) and 85
strikeouts. Entering the
2009 season, Santana was
Baseball America's choice as the top prospect in the Indians organization. Assigned to the Aeros of the AA-level
Eastern League, he played in 130 games, batted .290, 413 OBP, .530 SLG, 23 home runs, 90 BB and 83 strikeouts. and was named the Indians' 2009 Minor League Player of the Year − also known as the "
Lou Boudreau Award".
Baseball America ranked Santana as the organization's top prospect for the second time entering the 2010 season. The club assigned him to the
Triple-A Columbus Clippers, where he hit .316 with 13 home runs and 51 RBI in 57 games prior to his first
major league callup.
Cleveland Indians 2010−11 The
Indians promoted Santana on June 11, 2010, to make his MLB debut. Santana recorded his first major league hit in his second game, on June 12, 2010, a two-out, two-RBI double in the second inning off
Washington Nationals pitcher
J. D. Martin. In his next at-bat, Santana hit his first major league home run to right field in the bottom of the fifth inning. On August 2, 2010, Santana was injured in a game at
Fenway Park while defending home plate against
Boston Red Sox baserunner
Ryan Kalish. While attempting to dislodge the ball from Santana's mitt, Kalish slid into his left knee, bending it to the side. Santana was unable to walk off the field and had to be removed on a cart. Tests revealed that Santana had a high-grade sprain of his LCL and a hyperextension of his left knee. The injury ended Santana's rookie season. Santana started a
triple play against the
Chicago White Sox on April 3,
2011 with a diving catch off of an
Alexei Ramírez bunt. On April 29, 2011, Santana hit his first major league
grand slam, a
walk-off to defeat the
Detroit Tigers, 9−5. Santana finished 2011, which was his first full season in the major leagues, with 27 home runs, setting a club record for home runs hit by a switch hitter, and played 66 games at first base. He also hit 79 RBI, 35 doubles, and added 97 walks. He was one of four hitters in 2011 to reach 25 home runs, 35 doubles, and 90 walks, joining
Miguel Cabrera,
Prince Fielder, and
Joey Votto.
2012 On April 10,
2012, the Indians signed Santana to a five-year, $21 million contract with a club option for the 2017 season. Heading into the All-Star break, Santana was hitting .221, five home runs and 30 RBI in 69 games.
Manager Manny Acta spoke of the hopes the Indians had for their catcher but admitted he was not hitting "the way we expected him to hit." When Santana hit a home run in a July 18 game versus the
Tampa Bay Rays, it was his first since May 15. He later added on a single and finished the game with a season-high four RBI, his first multi-RBI game since May 11. "I know Santana feels so much better to get that monkey off his back. That power drought had been weighing on him", Acta remarked after the game. He hit two home runs in the game, his third career multi-home run game and first of the season since April 8.
2013−2016 In
2013, Santana and the newly promoted
Yan Gomes split the catching duties nearly evenly, with Santana seeing significant time at first base and designated hitter when Gomes was catching. With the emergence of Gomes' defensive prowess, Santana saw less and less time at catcher. Santana started
2014 playing primarily third base, a position he had not played since single-A, with some time at catcher. After a stint on the 7-day concussion DL in early June, he played exclusively at first base for the remainder of the season and into
2015. In 2014, he reached a career-high 113 walks while also leading the major leagues, and placed tenth in the AL with 241 times on base. He became the first switch hitter since
Lance Berkman in 2004 to achieve at least 25 home runs with 100 walks in the same season, and the fifth Indians switch hitter to do accordingly. On September 21,
2016, Santana hit his 150th career home run, doing so against the
Kansas City Royals. During the regular season, Santana batted .259, 34 home runs, 87 RBI and .865 OPS. He produced 30 home runs and 68 RBI when batting left-handed. Santana homered twice in the
2016 American League Championship Series versus the
Toronto Blue Jays. He also recorded the final out of the Series by catching a
Troy Tulowitzki pop-up in foul territory, sending the Indians to the
World Series. The
Chicago Cubs defeated Cleveland in the World Series in seven games. The Indians exercised their $12 million option for 2017. During the first 84 games of the season, he hit .238 with 10 home runs. In August and September, the club won an American League-record 22 games in a row, and Santana hit .365/.484/.689 during the streak. He had hit 13 home runs and 313/.429/.596 through that point in the second half of the season. Overall in 2017, he batted .259/.363/.445, 112 OPS+, 90 runs scored, 23 home runs, 79 RBI, 88 BB, 94 strikeouts, and five stolen bases. With significant improvement on defense, he led AL first basemen in total zone runs (13) and assists (95), was second in double plays (129), fourth in putouts (1,055), and fifth in fielding percentage (.996). The Indians won an AL-best 102 games for the regular season, but were defeated by the
wild-card qualifying
New York Yankees in the
ALDS. He won his first career
Wilson Defensive Player of the Year Award at first base, given to the top defensive player in the major leagues at each position. He was also named a finalist for the American League
Rawlings Gold Glove Award at first base.
Philadelphia Phillies On November 2, 2017, Santana filed for
free agency. On December 20, he signed a three-year contract with the
Philadelphia Phillies that included a team option for the 2021 season. The value of the three guaranteed seasons was $60 million. Santana reached 1,000 hits for his career on April 7, 2018, with a three-run home run in a 20−1 win versus the
Miami Marlins at
Citizens Bank Park. For the season, he batted .229 and had the lowest
batting average on balls in play (.231) of all major league players, and was second in the major leagues in walks per strikeout (1.18).
Return to Cleveland On December 3,
2018, the Phillies traded Santana and
J. P. Crawford to the
Seattle Mariners for
Jean Segura,
Juan Nicasio, and
James Pazos. In a three-team transaction ten days later, the Mariners traded Santana with cash to the
Indians, the Indians sent Encarnación and a competitive balance draft pick to the Mariners,
Yandy Díaz and
Cole Sulser to the
Tampa Bay Rays, and the Rays traded
Jake Bauers to Cleveland. Santana hit the 200th home run of his career on April 28, 2019, versus
Wade Miley of the
Houston Astros. Selected by fan voting in 2019 to his first career
MLB All-Star Game, Santana was named the starting first baseman for the American League. He and Indians were hosts for the event played at
Progressive Field and he batted cleanup. Santana also competed in the
Home Run Derby. On August 11 versus the
Minnesota Twins, he hit a game-winning grand slam in a 7–3 outcome to tie the Indians and Twins for first place. The following night, Santana hit a walk-off home run at Progressive Field to defeat the
Boston Red Sox, 6–5, that allowed the Indians to reclaim sole possession of first place in the AL Central for the first time since the previous April. Through August 15, Santana homered five times in the seventh inning or later to give the Indians a lead. The Indians declined their club option on Santana's contract for the 2021 season on October 30, 2020, making Santana a free agent.
Kansas City Royals On December 8, 2020, Santana signed a two-year, $17.5 million contract with the
Kansas City Royals. He was immediately inserted into the Royals lineup at first base; no player had started more than 55% of the team's games in a season at first base since
Eric Hosmer left the franchise after the 2017 season. Santana made 136 starts at first base during the 2021 season, and in 158 games overall, he hit .214/.319/.342 with 19 home runs and 69 RBI for a career-low
OPS+ of 80. His wRC+ of 83 was 7th-worst in the league among qualified hitters, although it was better than two of his Royals teammates. His 86 walks were good for sixth in the American League, and were the most by a Royals hitter since
José Offerman in 1998. Santana did play a portion of the season with a leg injury, although he was never placed on the injured list. Santana remained the Royals' first baseman entering the 2022 season. The Royals were 26–45 at the time of his trade away from the organization, and Santana was hitting .216/.349/.341 with four home runs and 21 RBI in 52 games, although in a season in which league-wide offensive numbers were down, his OPS+ was at 98.
Seattle Mariners On June 27, 2022, the Royals traded Santana to the
Seattle Mariners in exchange for
Wyatt Mills and William Fleming. In 79 appearances for the Mariners, Santana batted .192/.293/.400 with 15 home runs and 39 RBI.
Pittsburgh Pirates On November 29, 2022, Santana signed a one-year contract with the
Pittsburgh Pirates. On June 30, 2023, in a game against the
Milwaukee Brewers, Santana hit a walk-off two-run home run into the
Allegheny River to win it 8–7. It was the 69th home run hit into the Allegheny River in the history of
PNC Park. In 94 appearances for Pittsburgh, Santana batted .235/.321/.412 with 12 home runs, 53 RBI, and six stolen bases.
Milwaukee Brewers On July 27, 2023, the Pirates traded Santana to the
Milwaukee Brewers in exchange for minor-league shortstop Jhonny Severino. On September 23, Santana hit his 300th career home run off of
A. J. Puk of the
Miami Marlins. In 52 games for Milwaukee, he batted .249/.314/.459 with 11 home runs and 33 RBI. He became a free agent following the season.
Minnesota Twins On February 7, 2024, Santana signed a one-year, $5.25 million contract with the
Minnesota Twins. He played in his 2,000th career game on June 21, 2024, batting 1-for-4 with a double at the
Oakland Coliseum. In 150 games, he batted .238/.328/.420 with 23 home runs and 71 RBI. Defensively, he led AL first basemen in games (146), assists (92), and total zone runs (10), and ranked third in putouts (998).
Third stint with Cleveland On December 23, 2024, Santana signed a one-year, $12 million contract with the
Cleveland Guardians. During May, he collected 22 RBI—tying his career-best for any month—and also slashed .307/.448/.507/.955. By authoring a 10-game
hitting streak, Santana became the first player aged 39 or older since
Eddie Murray in
1996 to accomplish the feat for Cleveland. In 116 appearances for Cleveland, he batted .225/.316/.333 with 11 home runs, 52 RBI, and seven stolen bases. On August 28, Santana was released by the Guardians.
Chicago Cubs On August 31, 2025, Santana signed a one-year major league contract with the
Chicago Cubs. He appeared in eight games for the Cubs, going 2-for-19 (.105) with two RBI.
Arizona Diamondbacks On February 10, 2026, Santana signed a one-year, $2 million contract with the
Arizona Diamondbacks. ==International career==