Santos signed with the Detroit Tigers as a non-drafted free agent in 1995. In 2001, Santos was named Tigers Rookie of the Year.[2] Although he allowed some unearned runs, Santos posted a 0.00 ERA over his first 27.1 innings in the majors, the longest such streak to start a career since Fernando Valenzuela of the Los Angeles Dodgers in 1980–81 (34 innings). For his effort, he was named Detroit rookie of the year by the Detroit Sports Broadcasters Association.
Santos was traded to the Colorado Rockies for José Paniagua in 2002 and acquired by the Texas Rangers before the 2003 season. Then he signed a minor league contract with the Milwaukee Brewers before being called up for the 2004 season, where he earned his way onto the starting rotation. After two years with Milwaukee, he made an unusual route via the Kansas City Royals and the Rule 5 draft onto the major-league roster of the Pittsburgh Pirates for the 2006 season.
The Pirates granted him free agency on October 6, 2006, immediately after the 2006 season ended. On January 8, 2007, he signed a minor league deal with the Reds. On September 7, 2007, he was traded to the Baltimore Orioles for cash considerations.
Santos elected free agency on October 12, 2007. On January 11, 2008, Santos signed with the San Francisco Giants to a minor league contract with an invitation to spring training. He became a free agent at the end of the season. After splitting the 2009 season between the independent Newark Bears and the Vaqueros Laguna, he played with the Vaqueros again in 2010, appearing in 10 games with a 3–4 record.
