[4] After some years of trading with the Omaha while working with Peter Sarpy, the younger La Flesche was adopted as a son by the chief Big Elk.

[2] La Flesche and Mary stressed the importance of education for their children: Louis, Susette, Rosalie, Marguerite and Susan,[5] and "favored assimilation".

[5] From 1862 to 1869, La Flesche attended Presbyterian Mission Boarding Day School on the reservation where she learned to read, write, and speak in English as well as cook and sew.

Susette's siblings also became professionals: Susan LaFlesche Picotte became the first Native American physician and founded the first privately funded hospital on an Indian reservation; and Rosalie La Flesche Farley became a financial manager for the Omaha nation, leasing grazing land that was excess to individual household needs.

Their half-brother Francis LaFlesche became an ethnologist for the Smithsonian Institution, writing about the Omaha and the Osage, and making original recordings of their traditional songs.

Since her paternal grandmother and uncle were Ponca, she and her father traveled to Oklahoma to investigate conditions after the tribe's forced removal from Nebraska to Indian Territory.

La Flesche worked with Thomas Tibbles, an editor with the Omaha World Herald, to publicize the poor conditions they found at the southern reservation: the Ponca had been moved too late in the year to plant crops, the government was late with supplies and promised infrastructure and improvements, and malaria was endemic in the area.

Tibbles' coverage of the chief's imprisonment was instrumental in gaining Standing Bear pro bono legal services by two prominent defense attorneys, including the counsel for the Union Pacific Railroad.

[5] Standing Bear successfully challenged the lack of grounds of his arrest and imprisonment, arguing before the United States District Court that Indians were persons under the law, and had all the rights of US citizens.

[6] Following the trial, La Flesche and her half-brother Francis accompanied Standing Bear and others on a speaking tour of the eastern United States, organized by Tibbles.

In 1881 Jackson published a book about US treatment of Native Americans entitled A Century of Dishonor, and in 1884 the novel Ramona, based on Indian issues in Southern California.

[2] Longfellow reportedly said of La Flesche, "This could be Minnehaha", referring to the legendary Indian heroine in his poem The Song of Hiawatha.

After their return to Nebraska, LaFlesche and Tibbles became interested in the growing Ghost Dance movement and issues among the restive Sioux bands.