On its way it passes the towns of Plain, Leavenworth, Peshastin, Dryden, Cashmere, Monitor, and Wenatchee, all within Chelan County.

Water from the Wenatchee River and its tributaries has been diverted for irrigation since 1891, mainly for orchards.

The Tumwater Canyon dam originally provided power to the original 2-mile (3.2 km)-long railroad tunnel used near Stevens Pass to get trains across the Cascade Mountains, it was later (starting in 1928) used to power the railroad's electrification from Wenatchee to Skykomish.

Toxic chemicals banned decades ago in Washington continue to linger in the environment and concentrate in the food chain, threatening people and the environment, according to three recent studies by the Washington state Department of Ecology.

In 2007, the Washington Department of Health advised the public to not eat mountain whitefish from the Wenatchee River from Leavenworth downstream to where the river joins the Columbia, due to unhealthy levels of PCBs.