He played in Major League Baseball (MLB) for the St. Louis Cardinals, Philadelphia Phillies, Detroit Tigers and Miami Marlins.

His first major league hit was a single off Cincinnati Reds starting pitcher Brett Tomko on July 5, 1998.

[5] On July 29, 2002, Polanco, Mike Timlin, and Bud Smith were acquired by the Phillies for Scott Rolen, Doug Nickle, and cash.

In 2007, Polanco set a new major-league record for second basemen by playing in his 144th consecutive errorless game on August 13, in a 7–2 loss to the Oakland Athletics.

[7] However, the next day, after conferring with the umpiring crew, the official scorer determined the error was instead charged to first baseman Marcus Thames.

[13] After declaring free agency, Polanco signed a three-year contract for $18 million to return to the Phillies, with a mutual option for a fourth year.

[15] On May 14, 2012, Polanco reached the 2,000 hit mark with an eighth-inning home run off David Carpenter of the Houston Astros.

[16] On December 20, 2012, the Miami Marlins and Polanco agreed to a one-year contract worth $2.75 million,[17] making him the second-highest paid player on the team.

In March 2015, he claimed to be "90 percent" retired but remained open to the possibility of returning to playing or launching a coaching career under the right circumstances.

Polanco joined the Los Angeles Dodgers front office as a special assistant in player development in 2019.

[23] In July 2008, while with the Tigers, Polanco became a naturalized American citizen, taking the oath of citizenship at Comerica Park.