Picotte was the daughter of Joseph La Flesche, an Omaha leader, and Mary Gale. Her family pursued selected forms of Euro-American education while negotiating intense pressure over land, governance, language, and identity.
She studied at Hampton Institute, founded for Black and Native students but committed to assimilation, then entered the Woman's Medical College with scholarship support tied to reform organisations and the Office of Indian Affairs. Graduating first in her class demonstrated ability; it did not make those institutions politically neutral.
After government service she married Henry Picotte and maintained private practice for Native and white patients while raising two sons. Her work shows Indigenous professionals exercising agency inside systems designed partly to transform their communities.