Kristen Schaal was born in Longmont, Colorado to a Lutheran family of a Dutch descent. She was raised on her family's cattle farm, in a rural area near Boulder. Her father is a construction worker and her mother is a secretary. Schaal also has a brother who is three years older. She graduated from Northwestern University, then moved to New York to pursue a comedy career. Five years later, in 2005, she had her first break when she was included in New York Magazine's The Ten Funniest New Yorkers You've Never Heard.
Gravity Falls creator Alex Hirsch has commented that "[For the voices] In terms of Mabel, I knew from the get-go that it’s got to be Kristen Schaal or there’s no show. I would’ve just stopped working. If we hadn’t gotten her, I would have probably quit." 
She cosplayed as Mabel (complete with light-up sweater from the theme song) during the San Diego Comic Con 2013. The outfit was made by Alex Hirsch's girlfriend, professional costume designer Manzi DeYoung.