Cusack attended the University of North Texas and graduated with a performing arts degree. She trained in opera, ballet, jazz and tap. Cusack is married to actor Paul Telfer.
After completing university, she accepted a job on the MS Queen Elizabeth 2, which changed the course of her career. In Manchester, England, she had her breakthrough role as Christine Daae in The Phantom of the Opera. Soon after this, she made her West End debut as Fantine in Les Misérables. She also appeared in the original West End productions of The Secret Garden and Personals. She appeared in the Off-Broadway revival of Carrie: The Musical as the gym teacher, Ms. Gardner.
Cusack later returned to America, and on December 12, 2006, joined the Chicago production of Wicked as the standby for the lead role of Elphaba. Impressed with her portrayal of the character, the producers asked her to star in the lead role on the show's first national tour, beginning in October 2007. Her role as standby was taken over by Jennifer DiNoia.
She began performances on tour, replacing Victoria Matlock, on November 6, 2007. She starred alongside Katie Rose Clarke as Glinda. After spending one year on tour, she left on November 2, 2008, and was replaced by Donna Vivino, who had been her standby.
Cusack was next seen in the Melbourne production in Australia, as the temporary standby for Elphaba: Amanda Harrison had taken a break from the show due to illness, and the standby, Jemma Rix, had been given the lead role. Cusack was with the company from June 10 to July 10, 2009. She left to begin rehearsals for South Pacific.
In 2009, Cusack played Nellie Forbush in the first national tour of South Pacific. Based on the 2008 Broadway revival, performances began September 18, 2009 in San Francisco. For this role Cusack was nominated for the Helen Hayes Award for Outstanding Lead Actress in a Non Resident Production.
In 2012, she played the role of Miss Gardner in the Off-Broadway revival of Carrie - The Musical, which began performances at the Lucille Lortel Theatre on January 31, 2012. Carrie played a limited run until April 8, 2012.
Cusack appeared as Dot/Marie in the Chicago Shakespeare Theater production of Sunday in the Park with George from September 26 to November 4, 2012.
Cusack appeared in the production of the new musical First Wives Club, based on the film, beginning in February 2015. The musical ran at the Oriental Theatre, Chicago, Illinois. Cusack played the role of Annie.
Cusack originated the role of Alice Murphy in the new musical Bright Star, written and composed by Steve Martin and Edie Brickell. She has been with the show since its workshop in July 2013 at the Powerhouse Theatre at Vassar College in Poughkeepsie, New York. Cusack performed in the show's world premiere at the Old Globe Theatre in San Diego in September 2014. She continued her role during its tryout run in Washington D.C. from December 2015 to January 2016.
Cusack made her Broadway debut in Bright Star, which opened on March 24, 2016. For her performance, Cusack won a Theatre World Award. She also received nominations for the Tony Award for Best Actress in a Musical, the Outer Critics Circle Award for Best Actress in a Musical, the Drama League Award for Distinguished Performance, and the Drama Desk Award for Outstanding Actress in a Musical. Cusack will reprise the Alice during the musical's North American tour stop in Los Angeles.