Congress authorized the school in 1882 as one of three new boarding schools modeled on Carlisle, at a cost of $150,000. It was renamed Haskell Institute in 1887 after Dudley Haskell, the Kansas congressman who secured its construction in Lawrence. The early decades brought harsh discipline. In 1889, the fifth superintendent in five years, Charles T. Meserve, drew criticism from the National Education Association after discharging employees, including the principal teacher. Students sent four protesting petitions to the Bureau of Indian Affairs in Washington. A federal investigator whitewashed the affair. Haskell received Kansas high school accreditation in 1927 and was classified as a vocational-technical school by 1935. The transformation accelerated in the 1960s, when Native American activists pressed for educational self-determination. In 1993, it was renamed Haskell Indian Nations University and began developing bachelor's degree programs in American Indian Studies, Business Administration, and Environmental Sciences.

Twelve campus buildings carry National Historic Landmark designation -- an extraordinary concentration for any educational institution. The oldest standing structure is Hiawatha Hall, constructed in 1898 by the United Methodist Church as a chapel, named for the Onondaga leader. The building has been closed for decades because the federal government has not allocated funds for repairs, despite its landmark status. Osceola and Keokuk Halls, the original 1884 dormitories, are named for a Seminole warrior ("Rising Sun") and a Sac and Fox leader ("Watchful Fox"). In 1992, faculty and students built the Haskell Medicine Wheel Earthwork on the north end of campus. The circle marks the astronomical locations of the summer and winter solstices and represents death, rebirth, balance, and healing. A replica carved in tile at the Haskell Cultural Center and Museum on the south end creates a spiritual balance across the entire campus.

The Haskell-Baker Wetlands spread across the south side of campus, home to 243 species of birds, 21 species of fish, and the endangered Northern Crawfish Frog. The wetlands serve as a critical feeding and breeding ground for migratory birds traveling between Canada and South America. On drier ground, Haskell's athletic legacy includes Jim Thorpe, who won double gold medals at the 1912 Olympics and is a member of the Pro Football, College Football, U.S. Olympic, and U.S. Track and Field Halls of Fame. From 1902 to 1919, Haskell won five of eleven football games against the University of Texas. The campus newspaper, the Indian Leader, is the oldest Native American student newspaper in the country. The school also houses the American Indian Athletic Hall of Fame and the renowned Rinehart Collection of photographs at the Haskell Cultural Center.

The university hosts events that draw visitors from across the country: the annual Haskell Indian Art Market, the Stories-n-Motion Film Festival, and the Haskell Commencement and Pow-Wow. In 1994, Congress designated Haskell and 31 other tribal colleges as land-grant institutions. By 2013, enrollment had reached approximately 1,000 students. But the institution continues to face challenges. Investigations have documented inadequate oversight, and in February 2025, a quarter of the staff was laid off mid-school year due to federal budget cuts. Haskell endures because the communities it serves insist that it endure. What began as a tool of cultural erasure has been reclaimed by the very people it was designed to transform. Allan Houser's sculpture Comrade in Mourning stands on campus as a reminder of what was lost. The Medicine Wheel stands as a declaration of what persists.