Santiago made his major league debut for the Tigers in 2002. Used mainly as a backup, he was still named to the 2002 Topps All-Star Rookie Roster. During his rookie season, Santiago hit first-inning lead-off home runs on consecutive days (June 3, 2002 and June 4, 2002). In the June 3 game, he hit a second home run in the seventh inning. In 2003, Santiago assumed the starting shortstop role for the Tigers.