He played in Major League Baseball (MLB) for the Chicago White Sox, Toronto Blue Jays, Los Angeles Dodgers, and New York Yankees.

[2] Between 2002 and 2005, Santos steadily worked his way up through the Diamondbacks' farm system all the way to Triple-A Tucson, where he hit 21 doubles and 12 home runs in 2005.

On December 27, 2005, Santos was sent to Toronto Blue Jays along with Troy Glaus in exchange for Miguel Batista and Orlando Hudson.

After his struggles at Triple-A Syracuse in 2006, Toronto assigned Santos to their Double-A affiliate, the New Hampshire Fisher Cats for the 2007 season.

Santos won the Home Run Derby preceding the Eastern League All Star game in 2007 at Dodd Stadium.

He became a free agent at the end of the season and signed a minor league contract with the Chicago White Sox,[4] but on March 20, 2009, was traded to the San Francisco Giants in exchange for future considerations.

Less than two weeks after the trade he was brought back to the White Sox organization and sent to extended spring training to convert from infielder to pitcher.

[2][5] Santos pitched at four levels of the Sox minor league system in 2009, beginning at the Single-A Kannapolis Intimidators and ending at Triple-A Charlotte Knights.

[7] He established a new Major League record with his 25th straight scoreless appearance on the road to start a season in a 6–3 win over the Baltimore Orioles at Camden Yards on August 11, 2011.

The Blue Jays designated Santos for assignment again on August 27, after he made two unsuccessful appearances with the big league club.

[21] Santos finished the 2014 season with a 0–3 record, 5 saves, 8.57 ERA, 29 strikeouts, and a 2.19 WHIP in 26 appearances totaling 21 innings pitched.