In the past Malheur Lake (located in the enclosed Harney Basin to the southwest) outflowed into the river.

It flows south through Malheur National Forest, then southeast past Drewsey and through Warm Springs Reservoir.

From Juntura it flows generally east past Vale, joining the Snake from the west approximately two miles (3 km) north of Ontario, Oregon.

[6] The name was attached to the river by French Canadian voyageur trappers working for the North West Company on the Snake County Expeditions of Donald Mackenzie as early as 1818 for the unfortunate circumstance that some beaver furs they had cached there were snatched by Indigenous people.

From here they sought more direct routes to the Deschutes River, where they turned south until reaching the Free Emigrant Road.

There are approximately 370 miles (600 km) of irrigation-related canals and ditches in the lower basin of the Malheur River and its tributary Willow Creek.