On July 18, 1999, Cabrera popped up to end David Cone’s perfect game.

In 2002, he led all major league ballplayers in errors, totaling 29.

In 2003, he finished second among the league shortstops in batting average (.297), slugging percentage (.415), runs batted in (80), and stolen base percentage (24-to-26). In addition, he was one of four Montreal Expos players to have played all 162 games in a season, and the first to do it twice. Also, his 17 home runs that season were the most ever by a shortstop in Expos history.

Since the Expos traded Cabrera to the Red Sox in 2004, he appeared in six of the seven MLB postseasons, and at least once with every team he spent the end of the season with (2004 with Boston, 2005 and 2007 with Los Angeles, 2008 with Chicago, 2009 with Minnesota, and 2010 with Cincinnati).

Following his 2004 World Series victory with the Red Sox, Cabrera signed as a free agent with the Los Angeles Angels. He replaced David Eckstein at shortstop.

Cabrera had a 63-game on-base streak in early-through-mid-2006, which was the sixth-longest streak of all time. Ted Williams holds the Major League record with 84 straight games reaching base. Cabrera also had a straight steal of home plate on July 2, 2006, the first such time it had been accomplished by an Angels player since 1997. Cabrera scored without a throw.

In 2007, Cabrera led qualified AL shortstops with a .983 fielding percentage and a league-low 11 errors, earning him the American League Gold Glove for shortstop, the first by an Angel shortstop since Jim Fregosi in 1967. Also, he stole 20 bases for the third straight year and the fifth time overall.

On November 19, 2007, he was traded to the Chicago White Sox along with cash considerations for Jon Garland. Cabrera’s one season with White Sox was marred with controversy: arguing with manager Ozzie Guillén, leaving the clubhouse early to avoid the media, calling the press box to have errors overturned, questioning his team’s attitude, and kicking dirt at Tampa Bay Rays pitcher Grant Balfour during an at-bat in Game 1 of the AL Divisional Series.

On March 6, 2009, Cabrera signed a one-year deal and played middle infield with the Oakland Athletics.

On July 31, 2009, Cabrera was traded to the Minnesota Twins with cash considerations for SS Tyler Ladendorf.

In 2009, Cabrera led all major league players in errors, with 25. He had a solid offensive year, finishing the season batting .284, with 186 hits (4th among all shortstops), and 77 RBIs (1st among AL shortstops and 4th out of all shortstops). His seventh-inning, two-run home run in the American League Central Division’s tiebreaker game on October 6, 2009, kept the Twins in the game, which they later won, 6–5, in the 12th inning, to advance to post-season play.

On February 1, 2010, Cabrera signed a 1-year contract with the Cincinnati Reds. Cabrera spent the season as the Reds shortstop and posted a .263 average with four home runs, 42 RBIs, and a .303 on-base percentage. Cabrera played in only 123 games due to a strained oblique muscle that kept him on the DL from August 3 to September 3. The injury continued to bother him in September and into the playoffs, culminating with Dusty Baker giving him the start in game three of the NLDS despite Cabrera mentioning pain. In the first inning Cabrera made a high throw to first that allowed a run to score. While on the disabled list, Cabrera spent one game in full batboy uniform, bringing balls to the umpire and collecting bats.

On February 10, 2011, Cabrera signed a one-year contract for $1 million with the Cleveland Indians. With Asdrúbal Cabrera in place at shortstop, Cabrera switched to playing second base. On June 12, 2011, Cabrera got his 2,000th hit in Yankee Stadium off of pitcher Freddy García.

On July 30, 2011, Cabrera was traded to the San Francisco Giants for minor league outfielder Thomas Neal. He was originally given the number 6, but opted to wear number 43, out of respect for J. T. Snow.

Cabrera became a naturalized U.S. citizen on May 19, 2011, in South Carolina. Cabrera, a Colombian national, had faced extra scrutiny when traveling through customs due to Colombia’s reputation for drug trafficking. As of 2014, he lives in Windham, New Hampshire.

On January 18, 2012, Cabrera announced his retirement on a radio show in his native home country of Colombia. In November of the same year, his brother Jolbert said Orlando could have come out of retirement and played for the Colombia national baseball team if they had advanced to the final round of the 2013 World Baseball Classic.