[1][2] Settle originated the role of Norma Valverde in Hands on a Hardbody, a 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 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.

[10] Settle originated the role of Becky in the musical Waitress, which opened on Broadway on April 24, 2016, at the Brooks Atkinson Theatre after premiering at the American Repertory Theater in August 2015.

[13][14] 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.

"[15] 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.

[19] In 2017, Settle portrayed Lettie Lutz, a bearded lady, in the biographical musical drama film The Greatest Showman, alongside Hugh Jackman, Zac Efron, and Zendaya.

In January 2022, it was announced that Settle would make her West End debut performing the role of Angelique/Nurse in the musical & Juliet for a three-month run from March 29 to June 18, 2022.

Directed by Jon M. Chu, the movie includes stars such as Cynthia Erivo, Ariana Grande-Butera, Jonathan Bailey, Michelle Yeoh, Jeff Goldblum and Ethan Slater, as well as feature the voice of Peter Dinklage as Doctor Dillamond.

On the 19th of June 2024, Settle returned to the role of Angèlique in "& Juliet" at The Sydney Lyric Theatre, after Casey Donovan left the cast to star as Deloris Van Cartier in the upcoming Sister Act musical.