He played in Major League Baseball (MLB) for the Baltimore Orioles, Detroit Tigers and Cincinnati Reds.

[2] On July 30, 2004, Simón was traded with Ricky Ledée to the San Francisco Giants for Felix Rodríguez.

[8] After being released, Simón signed with the independent Sultanes de Monterrey of the Mexican League.

[13] The same day, he became the Orioles' closer (due to bad pitching and a subsequent injury to Mike Gonzalez), and he notched his first save against the New York Yankees.

He immediately excelled in the role, and at the All-Star break he led the National League with 12 wins (against only three losses) to go with a 2.70 ERA.

[19] In the All-Star game, Simón pitched a scoreless third inning, allowing one hit and striking out one batter.

[20] He would win only three more games after the All-Star break, finishing at 15–10 with a 3.44 ERA in 32 starts, while throwing a career-high 196+1⁄3 innings.

[5] On December 11, 2014, the Reds traded Simón to the Detroit Tigers for Jonathon Crawford and Eugenio Suárez.

[21][22] On January 16, 2015, Simón and the Tigers avoided arbitration when the two parties agreed on a one-year contract worth $5.5 million.

[23] On August 20, 2015, Simón recorded his first career complete game shutout in the Tigers 4–0 win over the Texas Rangers.

[24][25] Despite finishing the season with a league-worst 5.05 ERA, Simón led the Tigers in wins (13) and innings pitched (187).

[26] On June 6, 2017, Simon signed with the Long Island Ducks of the Atlantic League of Professional Baseball.

On July 3, 2018, Simon signed with the Tigres de Quintana Roo of the Mexican Baseball League.

The slow curve has been clocked as low as 49 MPH, leading some analysts to call it an eephus pitch.

[29] In January 2011, Simón allegedly shot and killed Michel Castillo Almonte and wounded his 17-year-old brother during a New Year's Eve celebration in Luperón, Dominican Republic.