McDonald was born in West Berlin, Germany, the daughter of American parents, Anna Kathryn, a university administrator, and Stanley McDonald Jr., a high school principal. At the time of her birth, her father was stationed with the United States Army. McDonald was raised in Fresno, California, the elder of two daughters; her young sister, Alison, writes and directs for television and film. McDonald graduated from the Roosevelt School of the Arts program within Theodore Roosevelt High School in Fresno. She got her start in acting with Dan Pessano and Good Company Players, beginning in their junior company. In a feature article about her written when she was a child, she said that she knew she wanted to be involved in theater “when I had my first chance to perform with the Good Company Players Junior Company.” She also said that the people who have had the most impact on her life are “Good Company director Dan Pessano and my mother.” She studied classical voice as an undergraduate under Ellen Faull at the Juilliard School, graduating in 1993.

In films, McDonald has appeared in Beauty and the Beast (2017), Ricki and the Flash (2015), 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.

In May 2000, Audra McDonald appeared as “The Beggar Woman” in Lonny Price’s concert version of Stephen Sondheim’s Sweeney Todd: The Demon Barber of Fleet Street, performed at Avery Fisher Hall at Lincoln Center, New York, with the New York Philharmonic with George Hearn and Patti LuPone. She reprised the role in some performances of the March 2014 Lincoln Center concert production, again directed by Price, this time opposite Bryn Terfel and Emma Thompson. She performed three concerts, titled “Audra McDonald Sings Broadway”, in the Sydney Opera House in November 2015, which also included “The Facebook Song” by Kate Miller-Heidke.

McDonald married bassist Peter Donovan in September 2000. They have one daughter, Zoe Madeline Donovan, named after McDonald’s close friend and Master Class co-star Zoe Caldwell and the late Madeline Kahn. McDonald became close friends with Kahn after they filmed a TV pilot together, and she found out she was carrying a girl the same day she sang at Kahn’s memorial. McDonald and Donovan divorced in 2009.

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 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. In 2013, she appeared in the HBO documentary Six by Sondheim.

McDonald was 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 then four-time winning actress Angela Lansbury. 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. Her 2014 performance as Billie Holiday in Lady Day at Emerson’s Bar and Grill earned McDonald her sixth Tony award and made her the first person to win all four acting categories.

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 this production of Mahagonny won two Grammy Awards, for Best Opera Recording and Best Classical Album in February 2009.

McDonald is also no stranger to the opera stage. In 2006 she made her opera debut at the Houston Grand Opera performing Francis Poulenc’s La Voix humaine and the world premiere of Michael John LaChiusa’s one-woman opera Send (who are you? I love you). She had previously performed in the world premiere of John Adams’ I Was Looking at the Ceiling and Then I Saw the Sky which was given in concert, and can be heard on the 1997 recording of the opera. In 2007 she performed the role of Jenny Smith in Kurt Weill’s Rise and Fall of the City of Mahagonny at the Los Angeles Opera. Her performance was recorded and won the Grammy Award for Best Opera Recording in 2009. She appeared in a revised version of George Gershwin’s opera Porgy and Bess, at the American Repertory Theatre (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 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.

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.

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.

Since 2012, McDonald has served as host for the PBS series Live From Lincoln Center, for which she shared an Emmy Award for Outstanding Special Class Program with the show’s producers. On August 1, 2017, it was announced that she had been added to the main cast for the second season of The Good Fight, reprising her role as Liz Lawrence from The Good Wife season 4.

She married Will Swenson on October 6, 2012. On October 19, 2016, they became parents to a girl, Sally James McDonald-Swenson. She also has two stepsons.

In 2012, Audra McDonald received the Golden Plate Award of the American Academy of Achievement.

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.

McDonald played Mother Abbess in the 2013 NBC live television production of The Sound of Music Live!.

In 2014, she was featured in Lynn Nottage’s short play Poof!, alongside Tonya Pinkins. It was produced for radio and podcast by Playing On Air.

McDonald played Billie Holiday on Broadway in the play Lady Day at Emerson’s Bar and Grill in a limited engagement that ended on August 10, 2014. After previews that began on March 25, 2014, the play opened at the Circle in the Square Theatre on April 13, 2014. Of the play, McDonald said in an interview:

McDonald attended Joan Rivers’ funeral in New York on September 7, 2014, where she sang “Smile”.

She joined the Covenant House board of Directors in 2014. Covenant House oversees programs for homeless youth in 27 cities in six countries across the United States, Canada, and Latin America. Audra was the recipient of their 2018 Beacon of Hope Award.

She appeared at the Williamstown Theatre Festival, Williamstown, Massachusetts, in Eugene O’Neill’s play A Moon for the Misbegotten in August 2015, co-starring with her husband Will Swenson.

In 2016, McDonald starred on Broadway as the vaudeville performer Lottie Gee in a new musical titled Shuffle Along, or, the Making of the Musical Sensation of 1921 and All That Followed about the making of the 1921 musical Shuffle Along. Shuffle Along closed on July 24, 2016 and McDonald began a maternity hiatus at that time.

McDonald won the Tony Award for Best Performance by an Actress in a Leading Role in a Play for this role, making her the first person to earn six Tony Award wins for acting (not counting honorary awards) and the first person to win a Tony Award in all four acting categories. In her acceptance speech, “she thanked her parents for encouraging her to pursue her interests as a child.” She also thanked the “strong and brave and courageous” African-American women who came before her, saying in part, “I am standing on Lena Horne’s shoulders. I am standing on Maya Angelou’s shoulders. I am standing on Diahann Carroll and Ruby Dee, and most of all, Billie Holiday. You deserved so much more than you were given when you were on this planet. This is for you, Billie.” This performance was filmed at Cafe Brasil in New Orleans and broadcast on HBO on March 12, 2016. McDonald received a 2016 Emmy Award nomination for Outstanding Lead Actress in a Limited Series or Movie for her role in the broadcast.

On September 22, 2016, Audra McDonald was awarded the National Medal of Arts by President Barack Obama for 2015. The Award states, in part: “for lighting up Broadway as one of its brightest stars…. In musicals, concerts, operas, and the recording studio, her rich, soulful voice continues to take her audiences to new heights.”

McDonald had planned to make her West End debut as Holiday in Lady Day in June through September 2016, but after becoming pregnant she postponed these plans. She performed in Lady Day in June 2017 through September 9, 2017, at the Wyndham’s Theatre in the West End.

McDonald joined other Broadway stars including Lin-Manuel Miranda, Josh Groban, Idina Menzel, Laura Benanti, and Kristin Chenoweth in 2018 to record Singing You Home, a bilingual children’s album designed to benefit organizations that aid families separated at the border.

In October 2020, McDonald joined many other Broadway stars in a virtual voter education and letter-writing party sponsored by VoteRiders to raise awareness about voter ID requirements.

In June 2020, McDonald and a coalition of professionals from across the theatre industry launched Black Theatre United, an organization whose mission is to inspire reform and combat systemic racism within the theatre community and throughout the nation. Emphasizing four goals—awareness, accountability, advocacy, and action—BTU works at the community and national levels to elevate anti-racist causes and support the Black community through various resources and initiatives.