Santos was drafted out of Mater Dei High School in Santa Ana, California by the Arizona Diamondbacks in the first round of the Major League Baseball Draft. Between 2002 and , Santos steadily worked his way up through the Diamondbacks' farm system all the way to class AAA Tucson, where he hit 21 doubles and 12 home runs in 2005.
On December 27, 2005, Santos was sent to Toronto along with Troy Glaus in exchange for Miguel Batista and Orlando Hudson. In , he hit .214 with 5 HRs and 38 RBI in 128 games with Toronto's AAA affiliate, the Syracuse Chiefs. He attended the Blue Jays' spring training, but did not make the active 25-man roster. After his struggles at AAA Syracuse in 2006, Toronto assigned Santos to their AA affiliate, the New Hampshire Fisher Cats for the 2007 season.
On May 13, , Santos was claimed off waivers by the Minnesota Twins.