Spanger was born in Newbury, Massachusetts. She made her Broadway debut in 1995 in the musical Sunset Boulevard, following a half-year run in the pre-Broadway national tour of Jekyll & Hyde. She originated the role of Lois Lane (Bianca) in the Broadway revival of Kiss Me, Kate. In Chicago she played Roxie Hart, and in Urinetown, Hope Cladwell. In 2006, she originated the role of Holly in The Wedding Singer.
May 1, 2002, actor Michael C. Hall and Spanger married; he played Billy Flynn opposite her Roxie Hart in the Broadway musical Chicago, the summer after their wedding. The couple separated in 2005 and filed for divorce in 2006.
Spanger's television credits include: Ed, Becker, Egg: The Arts Show, Six Feet Under, Law And Order: SVU, Michael and Michael Have Issues, and Bored to Death. She also starred in the Showtime original movie musical Reefer Madness (2005), as the promiscuous Sally.
She appeared in Synecdoche, New York (2008), written and directed by Charlie Kaufman.
She originated the role of Sherrie in the Broadway musical Rock of Ages but took an extended leave from the production in early June 2009, for vocal rest, before permanently departing the production on June 29 for "personal reasons".
She more recently originated the role of Jovie in the stage musical adaption of Will Ferrell's Christmas comedy Elf, that ran on Broadway for nine weeks at the Al Hirschfeld Theater and closed on January 2, 2011. On September 8, 2015, Spanger joined the Broadway cast of Matilda the Musical as Mrs. Wormwood.