After 1851, relations between the Cheyenne and the U.S. government were nominally conducted under the Treaty of Fort Laramie. Still, the U.S. government remained unwilling to control white expansion into the Great Plains, particularly after the Pike's Peak Gold Rush began in 1859. European Americans displaced the Cheyenne from their lands in violation of the treaty, and consumed important resources of water and game. Increasing competition eventually led to armed conflict between the groups.

Little is known of Black Kettle's life prior to 1854, when he was made a chief of the Council of Forty-four, the central government of the Cheyenne tribe. The Council met regularly at the Sun Dance gatherings, where they affirmed unity.

Chief Black Kettle was a pragmatist who believed that U.S. military power and the number of immigrants were overwhelming and unable to be resisted. In 1861, he and the Arapaho surrendered to the commander of Fort Lyon under the Treaty of Fort Wise, believing he could gain protection for his people. The treaty was highly unfavorable to the Southern Cheyenne.

Ambitious, Chivington felt pressure from Governor Evans to make use of the Third Colorado Cavalry before their terms expired at the end of 1864. On November 28, Chivington arrived with 700 men at Fort Lyon. According to an eyewitness, John S. Smith:

Black Kettle moved south and continued to negotiate with U.S. officials. He achieved the Treaty of Little Arkansas River on October 14, 1865. By this document, the U.S. promised "perpetual peace" and lands in reparation for the Sand Creek massacre. However, its practical effect was to dispossess the Cheyenne yet again and require them to move to Indian Territory (present-day Oklahoma). Black Kettle's influence continued to wane. Roman Nose and his Dog Soldiers took a prevailing hard line and continued warfare.

Black Kettle's dwindling band proclaimed their Desire to live peacefully alongside European Americans. Black Kettle signed yet another treaty, the Medicine Lodge Treaty, on October 28, 1867. The Dog Soldiers continued their raids and ambushes across Kansas, Texas, and Colorado.

In response to the continued raids and massacres, General Philip Sheridan devised a plan of punitive reprisals. He planned to attack Cheyenne winter encampments, destroying both supplies and livestock, and killing any people who resisted. At dawn on the morning of November 27, 1868 (just two days short of the fourth anniversary of the Sand Creek massacre), Lieutenant Colonel George Armstrong Custer led his 7th Cavalry Regiment to attack Chief Black Kettle and his village along the Washita River in what is now western Oklahoma. Custer's troops killed more than 100 Native Americans, mostly Southern Cheyenne. While trying to cross the Washita River, Black Kettle and his wife were shot in the back and killed.

At dawn on November 29, Chivington attacked the Sand Creek reservation; the event became known as the Sand Creek massacre. Most of the warriors were out hunting. Following Indian agent instructions, Black Kettle flew an American flag and a white flag from his tipi, but the signal was ignored. The 3rd Colorado Cavalry killed 163 Cheyenne by shooting or stabbing. They burned down the village encampment. Most of the victims were women and children. For months afterward, members of the militia displayed trophies in Denver of their battle, including body parts they had taken for souvenirs.