Smallpox! Over 1/2 of everyone died.

The first notice of smallpox occurs in the journals of La Verendrye on March 26, 1736. His journal entry records that a group of Cree, living near Winnipeg, had all died of smallpox. The extent of this particular epidemic cannot be ascertained from the single reference. However, the extinction of an entire band must surely have been accompanied by similar fatalities among other groups of the people. 
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Another epidemic between 1780-1783, is better documented. Fur trader accounts speak of great mass of burials and report that at least one-half of the Cree died. This epidemic affected almost every tribe in the region who were in contact with the Hudson Bay traders. Through trade and warfare, the disease had spread to every known part of the country. 

An old Cree man whom explorer David Thompson encountered related that a Cree/Piegan war party had caught smallpox from the Snake Indians about 1780. More than half their number were killed by the disease. Thompson also related that, according to best information, the disease was caught by the Ojibwe and Dakota at about the same time.  From them it spread further so that more than one half of all of the northern plains and forest fringe tribes died. In addition to the human death toll, Thompson noted a peculiar coincidence in the decline of animal species -- bison, deer, moose, and even wild fowl became scarce for a few years before the supply returned to normal.
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Epidemics of smallpox seemed to happen about every thirty-five or forty years, with the next major epidemic of smallpox and measles happening from 1816 to 1818, greatly affecting the Cree and Ojibwe people. 

​While the majority of disease came from the east via voyageurs and the fur trade, one of the most famous outbreaks occurred between 1836 and 1840, when the American Fur Company steamboat S.S. St. Peter carried infected people and supplies into the upper Missouri Valley, bringing a new strain of smallpox from St. Louis to Fort Union. Tens of thousands of people died, and the disease spread to all corners of the upper Great Plains. Some bands, such as the Mandan, nearly became extinct as a result.

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READ MORE:  ANTHROPOLOGICAL PAPERS OF THE AMERICAN MUSEUM OF NATURAL HISTORY VOLUME XXXVII, PART II, THE PLAINS CREE, BY DAVID G. MANDELBAUM (1940)