Keenan-Bolger's regional credits include Johanna in Sweeney Todd: The Demon Barber of Fleet Street at the Kennedy Center Sondheim Celebration in 2002, along with productions at the Goodman Theatre, TheatreWorks and Sundance Theatre Program. In 2003, she originated the role of Clara Johnson in the pre-Broadway world premiere of the Craig Lucas/Adam Guettel musical The Light in the Piazza at Seattle's Intiman Theatre and Chicago's Goodman Theatre. She has performed Off-Broadway in Kindertransport, Little Fish and Summer of '42.

She has sung in concert at the Lincoln Center American Songbook Series and at the Michigan Theatre with Audra McDonald. Keenan-Bolger performed as Martha in the 2005 The Secret Garden World AIDS Day benefit concert. She appeared on the concept cast album of Bright Lights, Big City. She also participated in a reading of Shrek the Musical as Princess Fiona in 2007.

She has also appeared on Broadway in the revival of Les Misérables as street waif Éponine from October 2006 to April 2007, for which she received a Drama Desk Award nomination.

Keenan-Bolger was born in Detroit, Michigan. She is an alumna of the Mosaic Youth Theatre of Detroit and the Detroit School of Arts High School (formerly the Detroit High School for the Fine and Performing Arts). She is a graduate of the University of Michigan's musical theatre performance program. She is one of three children, all of whom are involved in the performing arts. Her brother, Andrew Keenan-Bolger, also graduated from the University of Michigan with a BFA in musical theatre in 2007. Already a Broadway veteran, Andrew joined the national touring company of The 25th Annual Putnam County Spelling Bee in the fall of 2007. Her sister, Maggie Keenan-Bolger, who wrote the noted play From the Inside, Out, studied theatre and gender and women's studies at Oberlin College and graduated in 2006.

Keenan-Bolger appeared in the Playwrights Horizons production of the new musical Saved with music and lyrics by Michael Friedman and a book by John Dempsey and Rinne Groff in 2008. She appeared in Bachelorette at the Second Stage Theatre and in Adam Bock's A Small Fire, opposite Michele Pawk and Reed Birney.

In 2011, she starred in the New York Theatre Workshop production of Peter and the Starcatcher, a stage adaptation of the 2004 best-selling children's novel of a similar name. She reprised the role of Molly in the Broadway transfer production of Peter and the Starcatcher, which played at the Brooks Atkinson Theatre from March 28, 2012 through January 20, 2013. Keenan-Bolger received Drama Desk Award and Tony Award nominations for her performance.

Keenan-Bolger played Laura Wingfield in the American Repertory Theater production of The Glass Menagerie alongside Cherry Jones, Zachary Quinto and Brian J. Smith, from February 2, 2013 through March 17, 2013. Keenan-Bolger reprised her role in the production's Broadway transfer, which ran from September 5, 2013 through February 23, 2014 at the Booth Theatre. She received a third Tony Award nomination for her performance.

Keenan-Bolger starred in the Lincoln Center production of Sarah Ruhl's The Oldest Boy, which began performances at the Mitzi E. Newhouse Theater on October 9, 2014.

She recently participated in a reading of "The Brave Little Toaster: The Musical" as the titular character. Others involved included Carol Channing, reprising her role as the Ceiling Fan. In early 2015, she is scheduled to appear in a live reading of Eric Carle's "Animals, Animals" for the Autistic Children's Trust in Bangor, Maine.