Settle was born Keala Joan Settle in Hawaii, the eldest of five children of Susanne (née Riwai), who is of Māori descent from New Zealand, and British-born David Settle. Settle was raised in the Mormon faith. She is an alumn of Southern Utah University (never graduated).
Settle made her Broadway debut in 2011 in Priscilla Queen of the Desert as Shirley and in the ensemble.
Settle originated the role of Norma Valverde in Hands on a Hardbody, a new musical which ran briefly on Broadway in 2013, and is based on the 1997 documentary about real people competing to win a new truck. The TheatreMania reviewer wrote: "...but Settle, as Norma, steals every scene she's in. The spectacularly bizarre lead-in to her big number, 'Joy of the Lord,' is more difficult to pull off than most Shakespearean monologues, and her solo vocals reveal a soulful, oversized gospel range that drives the Holy Spirit straight to the back of the theater. When she tearfully realizes what her faith in God may have wrought, it stings like a chigger bite. Settle's touching performance should go on the shortlist for every Best Featured Actress prize in town."For this role, Settle was nominated for the Outer Critics Circle, Drama Desk, and Tony Award for Best Featured Actress in a Musical. Additionally, she was awarded the Theatre World Award for Outstanding Broadway or Off-Broadway debut performance during the 2012-13 theatrical season.
Settle played the role of Madame Thenardier in the revival of Les Misérables, starting in March 2014, and ending on March 1, 2015.
She starred in the stage musical Waitress, which opened on Broadway at the Brooks Atkinson Theatre on April 24, 2016, as Becky. She played this role in the premiere production at the ART (Cambridge, Massachusetts) in August to September 27, 2015.
Settle played the role of Tracy Turnblad in the national tour of Hairspray. In the review of the tour stop at the Kennedy Center in 2005, the Washington Post reviewer wrote: " As for Settle, she is a fine Tracy, even if she looks too old for graduate school, let alone high school." She appeared in the national tour of the Lincoln Center production of South Pacific as Bloody Mary, starting in 2009.The reviewer for the Pioneer Press, Massachusetts, wrote: "Better cast is Keala Settle, who plays the conniving Tonkinese trader lady Bloody Mary with a rolling gait, the venom of viper and — buried deeply but achingly visible in strategic moments — the maternal fierceness of a lioness."
In November through December 2012, Settle played the role of Mrs. Fezziwig in the Pioneer Theatre Company (Salt Lake City) production of the musical A Christmas Carol.
She played the role of the Narrator in Joseph and the Amazing Technicolor Dreamcoat at the Ogunquit Playhouse, Ogunquit, Maine from July 31 to August 25, 2013.
Settle performed in the Encores! concert staging of Violet on July 17, 2013 with Sutton Foster, but did not move on to the Broadway revival due to taking the role Madame Thénardier in the revival of Les Misérables; she was replaced in Violet by Annie Golden.
Settle discussed her career path, noting that "...I really am not a musical theatre performer. I'm more an R&B singer and have been doing that my whole life. My mother is — well, was — also an R&B singer, in New Zealand....I was too busy wanting to sing backup or doing studio work singing chorus stuff, and singing backup for Gladys Knight in Vegas." Further, after her run in Hairspray, she stated that she "...didn't know how to live in that world..." and so for several years worked backstage with designers until she was cast in South Pacific.