The elder of two daughters, Audra began to study acting at a young age to counteract her diagnosis as "hyperactive." She studied classical voice at the Juilliard School of Music, graduating in 1993.

McDonald became a three-time Tony Award winner by the age of 28, placing her alongside Shirley Booth, Gwen Verdon, and Zero Mostel by accomplishing this feat within five years.

In 2004 she won her fourth Tony for her role in A Raisin in the Sun. She is now in the company of other four-time Tony Award winning actresses Angela Lansbury, Verdon, and Mary Martin.

In addition to her long list of stage credits, McDonald has acted in film and on television. She has also recorded three solo albums, in which she performs the works of the new generation of Broadway theatre composers, particularly Michael John LaChiusa, Adam Guettel, and Jason Robert Brown.

McDonald frequently appears in concert and has performed with a number of the most prestigious orchestras worldwide.