The conflict also resulted in the largest mass execution in U.S. history, when 38 Dakota men, convicted of murder and rape, were hanged in Mankato, Minnesota. This was the first major armed engagement between the U.S. and Dakota, though it would not be the last. It is also referred to as the Dakota Conflict, the U.S.-Dakota War of 1862 or the Sioux Uprising.

While a fight had broken out in Spirit Lake, Iowa (the "Spirit Lake Massacre") in 1857, most accounts trace the beginning of the Dakota Conflict to the killing of five whites by four young Dakota men on Sunday, August 17, 1862. The Dakotas had been hunting, but ended up stealing food from the settlement of Acton in Meeker County (near present day Grove City. Soon, they had killed several of the settlers, including women. This event caused an uproar among the Santee Sioux living on the reservation, and some warriors convinced a reluctant Chief Little Crow to lead further attacks.

Records conclusively show that more than 500 soldiers and settlers died in the conflict, though many more may are believed to have died in small raids or after being captured. Estimates for U.S. losses range up to 800, though there is no accurate accounting of deaths on either side of the conflict.

Six weeks later, 303 Sioux prisoners were convicted of murder and rape by military tribunals and sentenced to death. Some trials lasted less than 5 minutes, and the Dakotas had no one to explain the proceedings to them or to represent them. President Lincoln reviewed the trial records and distinguished between those who had engaged in warfare against the United States and those who had committed the crimes of rape or murder of civilians. He approved of the execution of 39 of the latter, and commuted the death sentences of the others, largely due to the pleas from Bishop Henry Whipple for clemency.The 38, for whom the evidence seemed strongest, were executed by hanging in a single day on December 26, 1862, in Mankato.

The mass execution was performed for all to see from a single scaffold platform. It was, and still is, the largest execution in the history of the United States. The bodies of the Indians were pronounced dead by the regimental surgeons and then they were buried in a long trench, which was dug in the sand of the riverbank. Before they were buried, however, a "Dr. Sheardown" supposedly removed some of the Indians' skin. Little boxes containing the skin were sold in Mankato after the hangings. Over the years, many "souvenir" pieces of skin have continued to be sold, some on eBay. Of course, most are hoaxes and are just hunks of pigskin.

At that time, there was a high demand for anatomical subjects, so several doctors attending the hanging asked for the bodies. One of those was Doctor William Worrall Mayo. The mass grave was re-opened and the bodies removed for distribution. As fate would have it, Mayo received Marpiya Okinajin (He Who Stands in the Clouds or Cut Nose), with whom he had a confrontation earlier in his career. The body of Marpiya Okinajin was brought to Le Sueur where Mayo dissected it in the presence of some medical colleagues. Afterwards, the skeleton was cleaned, dried and varnished; Mayo kept it in an iron kettle in his home office. The skull and other identifiable remains of Marpiya Okinajin have been returned to Morton, Minnesota, for reburial under the Native American Graves Protection and Repatriation Act.

The remaining convicted Indians stayed in prison that winter. The following spring, they were transferred to Rock Island, Illinois (near Davenport, Iowa) where they were held in a prison for almost four years. By the time of their release, one third of the Indians had died of disease. The survivors were sent with their families to Nebraska.