The Plains Ojibwa, Cree and Assiniboine tribes inhabited the prairies of what is now southern Manitoba. Culturally, they were related to Great Plains tribes living farther south. They were nomadic hunters whose complex culture was based primarily on the taking and processing of bison meat and hides. In the north, the population was more culturally akin to the Inuit people—they hunted caribou, fished and collected wild vegetables and berries in the summertime.

The first Europeans arrived in Manitoba in 1668. Two years later, King Charles II of England granted the charter that established the Hudson's Bay Company, which attempted to control the fur trade in most of western and northern Canada, including the region that is now Manitoba. It was not until 1812 that the first permanent settlers arrived in the province. Their attempts at farming often met with natural disaster, and they were subject to frequent harassment from the North West Company, which was engaged in a bitter struggle with the Hudson's Bay Company.

The Dominion of Canada was established in the 1860s, and the lands of the Hudson's Bay Company were scheduled to become part of the new confederation. A group of Metis and Native Americans led by Louis Riel became concerned that they would lose their territory after the area became part of Canada. Their Red River Rebellion erupted in 1868, and Riel's forces were successful in establishing their own government for a brief time. The uprising was eventually put down, but the rebels did win property and language rights as a part of the 1870 legislation that joined Manitoba to the rest of Canada. (Riel, however, was later hanged for taking part in a rebellion in Saskatchewan.)

The arrival of the railroads in the 1880s—and the immigrants of many nationalities and cultures who rode them—served to tie Manitoba even more closely to the rest of Canada. The railroads also raised its status as a breadbasket province that provided agricultural products to the nation. Even today, when manufacturing constitutes a good share of the province's economy (especially in Winnipeg), Manitoba still depends greatly on wheat and cattle for its prosperity.