During his career, Beltré played for the Los Angeles Dodgers, Seattle Mariners, Boston Red Sox, and Texas Rangers in Major League Baseball (MLB).

Originally signed as an amateur free agent, Beltré made his MLB debut with the Los Angeles Dodgers in 1998 at age 19.

On September 19, 2014, Beltré surpassed Vladimir Guerrero as the all-time MLB leader for hits by a Dominican player, a record since broken by Albert Pujols in 2019.

Having played 21 major league seasons and won the Rawlings Gold Glove Award five times, Beltré is notable for his defensive prowess and career longevity as well as his power hitting.

While working out at Campo Las Palmas in 1994, a Los Angeles Dodgers facility — one of the first of its kind for a Major League Baseball (MLB) team in the Dominican Republic — Beltré was spotted by scouts Ralph Avila and Pablo Peguero.

[5] During his first at-bat, Beltré hit a two-out run batted in (RBI) double off Angels starter Chuck Finley into left field to score Paul Konerko from second base to tie the game.

[2] At one point in the spring training prior to the start of the 1999 season, Beltré's agent, Scott Boras, commented to him that "he couldn't believe" his relatively rapid ascent to the majors and handling of "such a difficult position like third base" at age 20.

Dodgers general manager Fred Claire, whom MLB did not contact during their investigation, publicly expressed surprise and that he was unaware of the incident.

"[citation needed] After Beltré had batted .167 through April 10, Ted Miller of the Seattle Post-Intelligencer wrote that he might become one of the Mariners' greatest busts.

[citation needed] On July 23, 2006, against the Boston Red Sox, Beltré hit an inside-the-park home run, the first one ever in Safeco Field history.

He tied with Brandon Inge for the AL lead in errors by a third baseman, with 18, but ranked second in the league in assists, total chances, and range factor.

[22] In his first game after returning from the DL, teammate Ken Griffey Jr. conspired with those responsible for the Safeco Field public address system to have Beltré's at-bat intro music be the opening march from The Nutcracker Suite.

[25] While Beltré's career before coming to the Red Sox had been regarded as somewhat disappointing, he hit .321 with 28 homers and 49 doubles in 2010, benefiting from the hitter-friendly Fenway Park.

[33] He added a fourth playoff home run in Game 5 of the 2011 World Series when he went down to one knee chasing an outside curve ball from Chris Carpenter.

He joined Pablo Sandoval, Albert Pujols, George Brett, Reggie Jackson and Babe Ruth as the only players to hit a three-homer game in both the regular season and the postseason.

He led the American League in home runs, slugging (1.087), OPS (1.607), total bases (25), and extra-base hits (six) while producing the fourth-highest batting average.

It was his third monthly award with Texas, making him one of seven players to win multiple times with the Rangers, including Josh Hamilton (four), Rafael Palmeiro, Alex Rodriguez (both with three), Iván Rodríguez, Juan González and Rubén Sierra (two each).

[62] In a May 29 game against the Pittsburgh Pirates, Beltré hit a two-run home run off Juan Nicasio to give him 1,501 career RBI, making him the 54th player to reach the milestone, and the fourth third baseman.

[66] Beltré would once again show his signature home run knee drop after hitting a solo shot in the second inning in a game against the Houston Astros on September 13, 2016.

[67] Ten days later, his two-run home run in the eighth inning against the Athletics aided the Rangers in clinching the American League West division crown for the second year in a row and the seventh in franchise history.

Beltré responded by picking up the edge of the logo that marked the on-deck circle and moving it closer to where he had been standing, which prompted Davis to eject him.

[77] On April 5, 2018, Beltré doubled in the second inning versus the Oakland Athletics to pass Rod Carew as the all-time Latin-American hits leader.

[4] Beltré's signature home run swing included a drop to one knee when connecting with a breaking ball, particularly notable during Game 5 of the 2011 World Series in an at bat against Cardinals ace pitcher Chris Carpenter.

[81] Beltré explained that his arm was so strong that early in his career he was making many throwing errors; by planting his feet, he was able to improve his accuracy despite his lack of proper foot positioning.

[82] Another major league manager, Joe Maddon, compared the unique style of Beltré's defensive play to Ozzie Smith's "flair at shortstop", Stan Musial's "coiled batting stance" and the way Steve Carlton wrapped his left wrist before releasing a slider.

"[81] Commented Rangers bench coach Steve Buechele, "He's not your most conventional third baseman, he does things his own way and has developed his own style over his career but there's something to be said for his hand-eye coordination and his hands.

[84] During a game against the Red Sox on June 26, 2016, Sandy León hit a foul ball which landed in the first row in the stands, just out of Beltré's reach.

After a game in which he hit a grand slam that provided the decisive runs in a 5–2 win over the Athletics on August 15, 2016, he took a broom from the groundskeepers closet and began combing an area of infield dirt.

[87] On June 5, 2023, Beltré was named the honorary general manager for the Karachi Monarchs of the Baseball United league for their inaugural season.

He has donated to Dave Valle's Esperanza International as well as foundations established by other major-league players, including Robinson Chirinos, Eddie Guardado, Joakim Soria and Michael Young.