Goodwin first had roles in the NBC television programs Law & Order and Ed before appearing in the Comedy Central television movie Porn 'n Chicken. She later had substantial roles in the films Mona Lisa Smile, Win a Date with Tad Hamilton!, Walk the Line—in which she portrayed Vivian Liberto, Johnny Cash's first wife—and Birds of America. She also played Dori Dumchovic in the dark comedy Love Comes to the Executioner. Goodwin played a leading role as Margene Heffman, the third wife in a polygamous family, on the HBO original series Big Love, which concluded on March 20, 2011. Goodwin has done voice work in the Adult Swim series Robot Chicken, where her younger sister Melissa works as an animator.
In 2008, Max Mara honored Goodwin with a "Face of the Future" award, an award recognizing up and coming women in film.
Goodwin played Gigi in He's Just Not That into You, which was released in February 2009. For this role, she received a nomination for the People's Choice Award for Breakout Movie Actress. In April 2009 she began filming Ramona and Beezus, playing "Aunt Bea". The film was released on July 23, 2010.
From 2011 to 2017, Goodwin played a leading role in the ABC fantasy drama series Once Upon a Time. She played both the fairy tale heroine Snow White and her real world counterpart, schoolteacher Mary Margaret Blanchard. Goodwin and husband Josh Dallas exited the show at the end of its sixth season to move back to Los Angeles with their family. She and Dallas returned to the series for its series finale at the end of the seventh season.
Goodwin voiced Judy Hopps, the protagonist rabbit police officer in Disney's Zootopia as well as Fawn in Disney's animated film Tinker Bell and the Legend of the Neverbeast. She also voiced Gwen, a kitchen maid who wants to be an inventor, in the animated series Sofia The First.
In January 2017, Goodwin was cast as Marianne in the Los Angeles production of Constellations. The play ran from June 14 to July 23, 2017 at the Geffen Playhouse.
In 2019, Goodwin is set to appear in episodes of anthology series The Twilight Zone and Heartstrings.