The flagship Indian boarding school in the United States from 1879 through 1918. It took over the historic Carlisle Barracks, which was transferred to the Department of Interior from the War Department.

From 1879 until 1918, more than 10,000 Native American children from 140 tribes attended Carlisle.

The school's 1911 Annual Report included the results of an employment survey of 532 graduates and 3619 other ex-students. Tribes with the largest number of students included the Lakota, Ojibwe, Cherokee, Apache, Cheyenne, Alaska Native, and Iroquois Seneca and Oneida.

During the early 20th century, the Carlisle Indian School was a national football powerhouse, and regularly competed against other major programs such as the Ivy League schools Harvard, Pennsylvania, Cornell, Dartmouth, Yale, Princeton, Brown, and Army (West Point) and Navy (Annapolis). Coach Pop Warner led a highly successful football team and athletic program at the Carlisle School, and went on to create other successful collegiate programs.

The Carlisle Indian School exemplified Progressive Era values. Some believed Carlisle provided an excellent education.