He previously played for 11 different Major League Baseball (MLB) teams: the Cleveland Indians (1997–2002), Montreal Expos (2002), Chicago White Sox (2003, 2009), Los Angeles Angels of Anaheim (2004–2007), Boston Red Sox (2008), New York Yankees (2011), Oakland Athletics (2012–2013), New York Mets (2014–2016), Atlanta Braves (2017), Minnesota Twins (2017), and Texas Rangers (2018).

He worked long days alongside his father, Miguel, harvesting coffee beans and fruit from the age of 9 to 14.

[8] Colón was signed by the Cleveland Indians as an amateur free agent in 1993 and began his career in their minor league system.

[10] He played Triple-A ball with the Buffalo Bisons in 1997 and on June 21 became the only player in team history to throw a no-hitter at Sahlen Field, then called North AmeriCare Park.

The following year, he set the modern-day but unofficial major league record for throwing the most pitches (20) in a single at bat on June 26, 1998[12] against Ricky Gutiérrez, who eventually struck out.

Later that season, Colón won his only start of the 1998 American League Championship Series, pitching a four-hit, one-run complete game.

Before the 2003 season, Colón was traded to the Chicago White Sox with minor leaguer Jorge Nunez for Orlando Hernández, Rocky Biddle, Jeff Liefer and cash.

During the 2005 season, he went 21–8 with a 3.48 earned run average, and became the first Angels pitcher to win the Cy Young Award since Dean Chance in 1964.

[17] Due to a partially torn rotator cuff that he received in a playoff game against the Yankees in 2005, Colón spent much of the 2006 season on the injured list with soreness or inflammation in his right shoulder.

On April 21, 2007, his first start of the 2007 season following his return from the injured list, Colón pitched 7 innings, allowing one run on seven hits for his first win in 2007.

On February 25, 2008, Colón signed a minor league deal with the Boston Red Sox and was invited to spring training.

Colón agreed to a one-year, $1 million contract to return to the Chicago White Sox in January 2009, shortly after they traded Javier Vázquez to the Atlanta Braves.

[21] Colón made his comeback from off-season surgery to remove bone chips from his pitching arm elbow during the White Sox Spring training, in the Cactus League in Arizona.

Colón won his first start in his second stint in Chicago, pitching six strong innings of three-hit ball as the Sox blanked Minnesota 8–0 on April 11, 2009.

Colón did not pitch in 2010 due to ongoing right shoulder and elbow pain and damage to the rotator cuff, ligaments and tendons.

When he was injured, he was in the seventh inning of a shutout game, but he limped off the field after covering first base on a ground ball to Yankees first baseman Mark Teixeira.

On July 14 against the Blue Jays, Colón exited after recording only two outs in the first inning while yielding eight runs, the shortest outing of his career.

Colón's 2011 season was somewhat of a resurgence, going 8–10 with a 4.00 earned run average and a 1.29 walks plus hits divided by innings pitched ratio.

[31] He started the second game of the season for the Athletics in the Opening Series in Tokyo, Japan, throwing eight innings, giving up one run over three hits while recording six strikeouts.

[34] On August 22, 2012, MLB suspended Colón for 50 games after he tested positive for synthetic testosterone, a performance-enhancing substance in violation of the Joint Drug Prevention and Treatment Program.

He was the second major leaguer to be suspended within a two-week time frame for testosterone (along with San Francisco Giants star Melky Cabrera).

In 2015 against the Washington Nationals, Colón became the third opening day pitcher over 40 years old to strike out eight batters, after Cy Young and Nolan Ryan.

On April 12, 2015, against the Atlanta Braves, Colón hit a run-scoring single off Alex Wood, the 6th run batted in of his career.

[45] On September 5, 2015, Justin Bour of the Miami Marlins hit a chopper down the first-base line; Colón charged and made a behind-the-back flip to first for the out.

On October 21, 2015, Colón pitched 1+1⁄3 innings in relief to earn the win in game 4 of the 2015 National League Championship Series and help the Mets sweep the Chicago Cubs.

[51] On May 7, Colón hit his first major league home run, against the San Diego Padres at Petco Park off of James Shields.

At age 42 years and 349 days, Colón broke a record, becoming the oldest major league player to hit his first home run.

[62] On August 4, he threw a complete game against the Texas Rangers; at age 44, he became the oldest American League pitcher to record a nine-inning complete-game win since 45-year-old Nolan Ryan did the same in 1992.

On February 4, 2018, Colón signed a minor league contract with the Texas Rangers that included an invitation to spring training.

[78] On October 23, 2023, Colón was selected in the second round by the Karachi Monarchs, with the 16th overall pick of the 2023 Baseball United inaugural draft.