He has previously played in MLB for the Philadelphia Phillies, Kansas City Royals, Seattle Mariners, Pittsburgh Pirates, Milwaukee Brewers, and Minnesota Twins.

He plays with the Dominican Republic national team internationally, winning the gold medal in the 2013 World Baseball Classic.

After signing with the Los Angeles Dodgers, Santana received a bonus worth $75,000, taking a part of the money to buy his mother a house.

[2] On July 26, 2008, the Dodgers traded Santana and pitcher Jon Meloan to the Cleveland Indians for third baseman Casey Blake.

[5] 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.

[2] Behind the plate, he placed fifth in the league with a 30 percent caught stealing clip while helping to lead the club to a Southern Division title.

[8] 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.

[9] He batted third in the order, making him the first Tribe player to debut hitting third since Jim Norris in 1977, according to the Elias Sports Bureau.

[10] 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.

[11] On August 2, 2010, Santana was injured in a game at Fenway Park while defending home plate against Boston Red Sox baserunner Ryan Kalish.

Santana started a triple play against the Chicago White Sox on April 3, 2011 with a diving catch off of an Alexei Ramírez bunt.

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.

[25] After the Indians acquired Edwin Encarnación in free agency prior to the 2017 season, he took over as the team's designated hitter, and Santana played primarily first base.

[28] On September 10 versus the Baltimore Orioles, he drove in his 585th run, passing Omar Vizquel as the Indians' career RBI leader among switch hitters.

[31] 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).

[32] 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.

[38] Santana reached 1,000 hits for his career on April 7, 2018, with a three-run home run in a 20−1 win[39] versus the Miami Marlins at Citizens Bank Park.

[44] On December 3, 2018, the Phillies traded Santana and J. P. Crawford to the Seattle Mariners for Jean Segura, Juan Nicasio, and James Pazos.

[45] 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.

[47] 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.

[51] 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.

[49] Overall with the 2020 Cleveland Indians, Santana batted .199/.349/.350 with 8 home runs and 30 RBIs in 60 games, and led the American League in walks, with 47.

[57] His 86 walks were good for sixth in the American League, and he did play a portion of the season with a leg injury, although he was never placed on the injured list.

The Royals were 26-45 at the time of his trade away from the organization, and Santana was hitting .216/.349/.341 with 4 HR and 21 RBI in 52 games, although in a season in which league-wide offensive numbers were down, his OPS+ was at 98.

[60] 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 during that period that Indians assistant hitting coach Vic Rodriguez urged him to do so, because "if you have a consistent routine that works for you and you stick to it every day regardless of how good or bad a season you’re having, you’re going to be fine."

The approach was designed to hit the ball with more hard contact up the middle, rather than attempt to continuously pull it, helping to significantly improve in virtually every category.

"[70] Santana wears the number 41 in honor of Victor Martinez, who is also a former switch-hitting catcher who started his career with the Cleveland Indians.