The Hopewell Indians settled along the Saginaw River. The European explorers and missionaries arrived around 1650 and settled into river settlements. The name Saginaw is derived from an Ojibway term "O-Sag-e-non" or "Sag-in-a-we" that means "to flow out". It is believed that the phrase refers to the outflow of the Saginaw River into the Saginaw Bay. The Ojibway were one of the Late Woodland Indian cultures.

The American Fur Company established a trading post on the west side of the Saginaw River after the War of 1812. By the middle of the century, the population increased as German immigrants established agricultural settlements in the area.

The region grew in value due to the land's forests. By 1855 there were 23 sawmills in the area. They produced a hundred-million board feet of lumber a year. By the 1880s, two sawmills alone each produced over 50 million board feet.