During the 19th century, the valley was largely inhabited by bands of the Kalapuya tribe of Native Americans. As many as 90% of the Kalapuya may have died as a result of an epidemic of "fever and ague" that hit the area between 1830 and 1833.
The Hudson's Bay Company controlled the fur trade in the valley and the rest of Oregon Country in the 1820s and 1830s from its Columbia District headquarters at Fort Vancouver. Joint U.S.–British occupancy, in effect since the Treaty of 1818, ended in 1846 with the Oregon Treaty.
The Willamette Valley was connected to California's Central Valley by the Siskiyou Trail. The first European settlements in the valley were at Oregon City and Champoeg. The first institution of higher learning on the West Coast, today's Willamette University, was founded in the valley at Salem by Jason Lee, one of the many Oregon missionaries who settled in the valley.
A massively productive agricultural area, the valley was widely publicized from the 1820s as a 'promised land' of the 'flowing milk and honey' sort and became, at Oregon City, the destination of choice for the oxen-drawn wagon trains of organized emigrants traveling west on the perilous and rough 1,800 to 2,100 miles (2,900 to 3,400 km) of roadbeds of the Oregon Trail in the 1840s–1880s.
After the reports of the Lewis and Clark Expedition were published about 1807, a small steadily increasing stream of isolated pioneer groups began settling the valley and improving the explored road from the east set up by the fur traders and mountain men as they came. From the 1841 trail opening, when the effort of many over many years finally widened the fur traders' mule trails into an improved rough road just capable of carrying the width of a wagon, settlers charged into the region along the new trail, creating new settlements centered about colonial Oregon City as the early capital, even before ownership of the region was settled.
So many came, the valley led the way to achieving statehood in less than 16 years after its ownership was settled on the United States in 1846. A small part of the Willamette Valley eco region is in southwestern Washington around the city of Vancouver, which was once the site of an early colonial-era settlement—Fort Vancouver.
The Willamette Valley—served with its saw mills, lush productive farms, handy river transport network, and nearby timber and mineral resources—developed naturally as a cultural and major commercial hub, as the Oregon Country became the Oregon Territory. The valley forms the cultural and political heart of Oregon and is currently home to 70% of Oregon's population.