Dotel graduated from Liceo Cansino Afuera in the Dominican Republic and was signed by the New York Mets as an amateur free agent in 1993. He played for their minor league affiliate in the Dominican Summer League through 1994 and then promoted through the Mets’ minor league system for the next several seasons.

In November 1993, not long after Dotel signed his first contract with the New York Mets, his father was murdered. Emilio Dotel, 53, entered a taxi cab on his way home from work and was robbed, strangled, and killed. His body was found a day later 5 miles (8.0 km) from his house in Santo Domingo, Dominican Republic. The late Emilio Dotel and his wife, Maria Magdalena Dotel, had three sons and two daughters.

On December 23, 1999, Dotel was traded by the Mets with Roger Cedeño and minor leaguer Kyle Kessel to the Houston Astros for Mike Hampton and Derek Bell.

In 2000 Dotel amassed three wins in 16 games started as well as 16 saves as his role converted from starter to relief pitcher for the Astros, filling in as closer for an injured Billy Wagner. This season marked the first time in National League history that a pitcher had over 15 starts and 15 saves (the only other season in MLB history came in the American League in 1999, when Tim Wakefield won six games in 17 starts and attained 15 saves for the Boston Red Sox).

In 2001, Dotel again began the season as a starter but moved into the bullpen as the setup man for closer Billy Wagner. Dotel had an excellent season in 2002; he led all relievers with 118 strikeouts and helped secure a well-reputed bullpen for the Astros at that time. By 2003, Dotel and Wagner were joined by future Astros closer Brad Lidge and all three partook in a historic event in which six Astros pitchers combined for a no-hitter against the New York Yankees on June 11, 2003.

After the 2003 season, Wagner was traded to the Philadelphia Phillies and Dotel started 2004 as the closer for the Astros.

On June 24, 2004, Dotel was traded to the Oakland Athletics in a three-team trade that sent Carlos Beltrán to the Astros, minor leaguer Mike Wood, Mark Teahen, and John Buck to the Kansas City Royals. Dotel served as closer for the Athletics and finished the 2004 season with a career-high 36 saves (22 for the A’s and 14 for the Astros).

Dotel began 2005 as closer for the Athletics again, but had a rough start and went on the 60-day disabled list on 19 May. He underwent Tommy John surgery on June 1, ending his season after just 15 games.

Dotel signed a one-year deal with the New York Yankees in December 2005. He missed the first four months of the 2006 season, recovering from his Tommy John surgery. Dotel had a setback after developing tendinitis in his elbow while on a rehab assignment with the Trenton Thunder. This pushed his return into August as he went through another minor league assignment with the Columbus Clippers. Dotel pitched his first game in a Yankees uniform on August 16, coming into the game in the eighth inning against the Baltimore Orioles, facing two batters with one strikeout and one walk. He finished the season playing in 14 games with no record and an ERA of 10.80.

Dotel became a free agent at the end of the 2006 MLB season. On December 8, 2006, he agreed to a one-year contract with the Kansas City Royals for $5 million.

On July 31, 2007 the Royals traded Dotel to the Atlanta Braves in exchange for pitcher Kyle Davies. He made his Braves debut on August 1, throwing a scoreless ninth inning in a 12–3 rout of the Astros. On August 10, Dotel was placed on the disabled list with a right shoulder strain. He made his return on September 22 escaping a bases-loaded jam which eventually led to a Braves win. He finished the season 2–1 with a 3.76 ERA.

On January 21, 2008 he agreed to a two-year, $11 million deal with the Chicago White Sox.

On January 21, 2010, Dotel agreed to a one-year, $3.25 million deal with the Pittsburgh Pirates, plus bonuses for games finished. The deal also included a club option for 2011 for $4.5 million with a $250,000 buyout. Dotel started the year as the Pirates closer and stayed the closer until he was traded. Dotel recorded 21 saves in 2010 with the Pirates.

On July 31, 2010, Dotel was traded to the Los Angeles Dodgers for James McDonald and Andrew Lambo. He appeared in 19 games with the Dodgers and had a 3.38 ERA and one save.

On September 18, 2010, Dotel was traded to the Colorado Rockies for a player to be named later. Dotel was ineligible to play on the postseason roster, but it made no difference as Colorado missed the playoffs. Dotel finished playing in eight games with the Rockies, going 0–1 with a 5.06 ERA.

Dotel agreed to a one-year, $3.5 million deal with the Toronto Blue Jays with a club option for 2012. He earned his 50th career victory on April 8, 2011 against the Los Angeles Angels of Anaheim.

On July 27, 2011, Dotel was traded to the St. Louis Cardinals with Edwin Jackson, Marc Rzepczynski and Corey Patterson for Colby Rasmus, P. J. Walters, Trever Miller and Brian Tallet. Dotel got his first championship title when the Cardinals beat the Texas Rangers in the 2011 World Series. On October 31, 2011 it was announced that Cardinals would not pick up his team option for the 2012 season, making Dotel a type A free agent.

Dotel signed with the Detroit Tigers on December 7, 2011. He made his debut for them on April 7, 2012. The Tigers were Dotel’s thirteenth major league team, allowing him to pass Matt Stairs, Mike Morgan and Ron Villone for the MLB record of the most teams for which a player played.

Dotel made his 700th appearance in a major-league game on April 21, 2012, in the nightcap of a double-header against the Texas Rangers.

On June 8, 2013, Dotel was placed on the 60-day DL due to right elbow inflammation.

On October 3, 2014, Dotel announced his retirement from professional baseball at the age of 40 after pitching 15 seasons for 13 MLB teams. His career strikeout rate of 10.8 per nine innings is the best in the history of baseball for right-handed pitchers with at least 900 innings pitched.

In August 2019, Dotel was arrested on charges related to a drug trafficking and money laundering operation, while Luis Castillo was cited for related charges. Later that month, a judge cleared Dotel and Castillo of the money laundering charges. Dotel still faces a charge for allegedly possessing an illegal weapon at the time of his arrest.