Whitman was born in Los Angeles, California, the daughter of Pat Musick, a voice artist, and Jeff Whitman, a personal manager and set construction co-ordinator. She started her career with a voice over for a Tyson Chicken commercial, a role her mother had also auditioned for.

At the age of four, Whitman made her film debut, acting alongside Meg Ryan in When a Man Loves a Woman. She played Ryan's daughter in the movie. She has had a role in Independence Day as the President's daughter, George Clooney's daughter in One Fine Day and in Hope Floats, with Sandra Bullock. She guest starred in the episode The One Where Rachel Quits of the sitcom Friends in 1996. During this time, Whitman attended Ribét Academy, a private preparatory school, in Los Angeles.

As a more mature actress, Whitman joined the cast of Thief for FX Networks, playing the stepdaughter of Nick Atwater (Andre Braugher). She was also featured in several video games, playing the role of Yuffie Kisaragi in the Square-Enix/Disney video game Kingdom Hearts II as well as an appearance in the third-person shooter RPG Dirge of Cerberus -Final Fantasy VII-.

Whitman made several high profile guest appearances in 2006 and 2007, including a stint on ABC's Grey's Anatomy as Heather, a girl who, at seventeen, suffered from severe curvature of the spine. She also appeared on Desperate Housewives as an unscrupulous friend of Julie's.

Whitman was initially cast in the 2007 series remake of The Bionic Woman, playing the deaf younger sister of the title character. On June 27, 2007, TV Guide reported that Whitman was being replaced in the role of Jaime's sister, and Lucy Hale was cast as Whitman's replacement the following July. An NBC spokesperson confirmed this, stating, "The decision was purely creatively driven. It is very common to change storylines, characters, actors after the initial pilot is shot." The sister character's hearing was restored after this recasting at the request of an NBC executive. Mae has also appeared in the recent episode of Law and Order: Special Victims Unit in the Season 9 episode "Streetwise" as an on-the-street-mother who adopts street children forming a homeless family.

Mae Whitman was the voiceover for Katara of the Water Tribe in the animated show "Avatar: The Last Airbender", and previously Rose in "American Dragon: Jake Long." She has appeared most recently in the HBO series "In Treatment," as Rosie.

She is also Cynder in The Legend of Spyro, The Eternal Night.

As part of a deal to promote the Disney production of Tinker Bell, at 0100GMT on Sunday 26th October 2008, the UK's speaking clock started to use Mae's voice.

• In Treatment (TV series) as Rosie
• Arrested Development(TV series) as Ann Veal
• Lost in the Dark (TV movie)
• The Judds (TV mini-series)
• Degree of Guilt(TV mini-series)
• Hope Floats
• One Fine Day
• Invisible Child
• State of Grace(TV series) as Emma Grace McKee
• A Season for Miracles
• Chicago Hope (TV series)
• JAG(TV series)
• Duckman(cartoon, voice-over)
• Independence Day
• Early Edition(TV series)
• Friends(TV series)
• Judging Amy(TV series)
• Providence (TV series)
• Johnny Bravo(cartoon, voice-over)
• Superman: The Animated Series (cartoon, voice-over)
• The Jungle Book 2(animated film, voice-over) as Shanti
• American Dragon: Jake Long(cartoon, voice-over) as Rose
• Avatar: The Last Airbender (cartoon, voice-over) as Katara
• The Happy Elf (cartoon, voice-over)
• Cold Case (TV series)
• Thief(TV series)
• Desperate Housewives (TV series)
• Grey's Anatomy(TV series)
• Bionic Woman (TV series, unaired pilot)
• Boogeyman 2(2008 film) as Alison
• Ghost Whisperer (TV series)
• Law and Order: Special Victims Unit(TV series)
• Tinker Bell(CGI animated direct-to-video movie) as the titular character
• Nights in Rodanthe as Amanda Willis