Callies was born in La Grange, Illinois, the daughter of Valerie Wayne, a professor of English, and David E. Callies, a law professor. Callies moved to Honolulu, Hawaii with her family when she was one. Her parents are professors at the University of Hawaii, Manoa. Throughout her youth, she expressed an interest in acting through participating in various school plays at the independent Punahou School. After graduating from high school, she entered Dartmouth College in Hanover, New Hampshire. In conjunction with her studies, she continued her involvement in theatre. She continued her education at Denver's National Theater Conservatory, where she obtained her Master of Fine Arts degree in 2002.
"As hard as we all tried, the Prison Break powers that be and I were unable to find a way to meet both the needs of the story and the needs of my family. We parted wishing each other well. I had a wonderful time working with the creative team and have a world of respect for all of them; they took great care of Sara. I'm also enormously grateful to the fans. They've been so gracious and supportive, and I hope they continue to enjoy the show."
However, in March 2008, Olmstead stated that the character of Sara is still alive and would return in Season 4 of Prison Break. Though the character Sara Tancredi appeared to have a violent death, Olmstead stated "...we realized that there was actually a way she could still be alive." When asked by Kirstin of E! whether the fans' overwhelming response to her death had factored in, Executive Producer Matt Olmstead admitted it had indeed influenced the decision.
On July 21, 2002, Callies married Josh Winterhalt, whom she met at Dartmouth College. Winterhalt is a martial arts teacher. On January 23, 2007, her publicist announced that the couple were expecting their first child. In July 2007, Callies gave birth to a girl, Keala Winterhalt.
She was voted one of Maxim's "The Hottest Women of Fall TV '08."