McDonald graduated from the Roosevelt School of the Arts program within Theodore Roosevelt High School in Fresno.
She studied classical voice as an undergraduate under Ellen Faull at the Juilliard School, graduating in 1993.
She got her start in acting with Dan Pessano and Good Company Players, beginning in their Junior Company. "I knew I wanted to be involved in theater when I had my first chance to perform with the Good Company Players Junior Company." "The people who have had the most impact on my life: Good Company director Dan Pessano and my mother."
McDonald became a three-time Tony Award winner by age 28 — for her performances in Carousel, Master Class, and Ragtime, placing her alongside Shirley Booth, Gwen Verdon and Zero Mostel by accomplishing this feat within five years. She was nominated for another Tony Award for her performance in Marie Christine before she won her fourth in 2004 for her role in A Raisin in the Sun, placing her in the company of other four-time winning actresses Gwen Verdon and Mary Martin. She reprised her Raisin role for a 2008 television adaptation, earning her a second Emmy Award nomination. On June 10, 2012, McDonald scored her fifth Tony Award win for her portrayal of Bess in Broadway's The Gershwins' Porgy and Bess, thus tying Angela Lansbury and Julie Harris.
McDonald appeared as Lizzie in the Roundabout Theatre Company's 2007 revival of 110 in the Shade, directed by Lonny Price at Studio 54, for which she shared the Drama Desk Award for Best Actress in a Musical with Donna Murphy. On April 29, 2007, while she was in previews for the show, her father was killed when an experimental aircraft he was flying crashed north of Sacramento, California.
McDonald appeared in a revised version of Porgy and Bess, at the Loeb Drama Center (in Cambridge, Massachusetts) from August through September 2011, and recreated the role on Broadway at the Richard Rodgers Theatre, which opened on January 12, 2012 and closed on September 23, 2012. For this role, McDonald won her fifth Tony Award and her first in a Leading Actress category.This American Repertory Theater production was "re-imagined by Suzan-Lori Parks and Diedre Murray as a musical for contemporary audiences."
McDonald has maintained ties to her classical training and repertoire. She frequently performs in concert throughout the U.S. and has performed with musical organizations such as the New York Philharmonic and the Mormon Tabernacle Choir. Carnegie Hall commissioned the song cycle The Seven Deadly Sins: A Song Cycle for McDonald, and she performed it at Carnegie's Zankel Hall on June 2, 2004. She sang two solo one-act operas at the Houston Grand Opera in March 2006- Francis Poulenc's La Voix Humaine and the world premiere of Michael John LaChiusa's Send (who are you? I love you). On February 10, 2007, McDonald starred with Patti LuPone in the Los Angeles Opera production of Kurt Weill's opera Rise and Fall of the City of Mahagonny directed by John Doyle. The recording of the Los Angeles Opera production of Kurt Weill's opera Rise and Fall of the City of Mahagonny, featuring McDonald and Patti LuPone, won two Grammy Awards, for Best Opera Recording and Best Classical Album in February 2009.
In September 2008, American composer Michael John LaChiusa was quoted in Opera News Online, as working on an adaptation of Bizet's Carmen with McDonald in mind.
McDonald has recorded five solo albums for Nonesuch Records. Her first, the 1998 Way Back to Paradise, featured songs written by a new generation of musical theatre composers who had achieved varying degrees of prominence in the 1990s, particularly LaChiusa, Adam Guettel and Jason Robert Brown.
Her next album, How Glory Goes (2000), combined both old and new works, and included composers Harold Arlen, Leonard Bernstein and Jerome Kern. Her third album, Happy Songs (2002), was big band music from the 1920s through the '40s. Her fourth album, Build a Bridge (2006), features songs from jazz and pop.
In May 2013, Audra McDonald released her first solo album in seven years, Go Back Home, with a title track from the Kander & Ebb musical The Scottsboro Boys. To coincide with the album's release, McDonald performed a concert at Avery Fisher Hall in New York City that aired on the PBS series Live from Lincoln Center titled Audra McDonald In Concert: Go Back Home.
At the 2010 BCS National Championship Game on January 7, McDonald sang America the Beautiful for the sold-out stadium fans to celebrate the final game of the college football season.
McDonald has also made many television appearances, both musical and dramatic. In 2001, she received her first Emmy Award nomination for Outstanding Supporting Actress in a Miniseries or TV Movie for the HBO film Wit, starring Emma Thompson and directed by Mike Nichols. She also has appeared on Homicide: Life on the Street (1999), Law & Order: Special Victims Unit (2000), Having Our Say: The Delany Sisters' First 100 Years (1999), the short-lived Mister Sterling (2003), The Bedford Diaries (2006), and Kidnapped (2006–2007), and in the 1999 television remake of Annie as Daddy Warbucks' secretary & soon-to-be wife, Miss Farrell. She sang with the New York Philharmonic in the annual New Year's Eve gala concert on December 31, 2006, featuring music from the movies; it was televised on Live from Lincoln Center by PBS.
McDonald appeared as Naomi Bennett in Private Practice, a spinoff of Grey's Anatomy. She replaced Merrin Dungey, who played the role in the series pilot. McDonald left Private Practice at the end of season four.
In films, McDonald has appeared in Best Thief in the World (2004), It Runs in the Family (2003), Cradle Will Rock (1999), The Object of My Affection (1998), and Seven Servants by Daryush Shokof which was her film acting debut in (1996).
McDonald played Mother Abbess in the NBC production of The Sound of Music Live!