Isringhausen signed with the Cardinals as a free agent before the 2002 season. During Isringhausen's time with the team, the Cardinals won the Central Division in 2002, 2004, 2005, and 2006 with World Series appearances in 2004 and 2006, winning the World Series in 2006. He registered a league-leading 47 saves in 2004, tying the franchise record which Lee Smith set, until Trevor Rosenthal broke the record in 2015. He was an All-Star and posted a 2.14 earned run average (ERA) with 39 saves in 2005 as the Cardinals won 100 games. The saves total was fifth in the NL.