She continued to work on her community's behalf until the end of her life, though much of that work seemed to be in vain, as her people lost many of their ancestral lands and became more, not less, dependent on the OIA. Picotte suffered for most of her life from chronic illness. In medical school, she had been bothered by trouble breathing, and after a few years working on the reservation, she was forced to take a break to recover her health in 1892, as she suffered from chronic pain in her neck, head, and ears. She recovered but became ill again in 1893, after a fall from her horse left her with significant internal injuries. Over time, Picotte's condition caused her to go deaf. As Picotte aged, her health declined, and by the time that the new reservation hospital was built in Walthill in 1913, she was too frail to be its sole administrator. By early March 1915, she was suffering greatly and died of bone cancer on September 18, 1915. The next day, services by both the Presbyterian Church as well as the Amethyst Chapter of the Order of the Eastern Star were performed. She is buried in Bancroft Cemetery, Bancroft, Nebraska near her husband, father, mother, sisters and half-brother. Picotte's sons went on to live full lives. Caryl Picotte made a career in the United States Army and served in World War II, eventually settling in El Cajon, California. Pierre Picotte lived in Walthill, Nebraska, for most of his life and raised a family of three children. In her career, Picotte served over 1,300 patients in a 450 square mile area. The reservation hospital in Walthill, Nebraska, now a community center, is named after Picotte and was declared a National Historic Landmark in 1993. The hospital has also been named as one of the 11 most endangered places of 2018 by the National Trust. Work is underway to raise funds for its restoration. An elementary school in western Omaha Nebraska is named after Picotte. On June 17, 2017, the 152nd anniversary of her birth, Google released a Google Doodle honoring Picotte. In 2018, a bust of Picotte was dedicated at the Martin Luther King Jr. Transportation Center in Sioux City.