Lake Como at 12,215 ft (3723m) in northern San Juan County, in the Uncompahgre National Forest in the northwestern San Juan Mountains is the headwaters of the river.

It flows northwest past Ouray, Ridgway, Montrose, and Olathe and joins the Gunnison at Confluence Park in Delta.

The major tributaries are all creeks draining the northwest San Juan Mountains.

The name Uncompahgre (/ʌnkʌmˈpɑːɡreɪ/ ⓘ) comes from the Ute word Uncompaghre, which loosely translates to "dirty water," "red lake," or "red water spring" and is likely a reference to the many hot springs in the vicinity of Ouray.

[6][7] In October 2020, the City of Montrose announced a multi-year, multi-million dollar river restoration project along the Uncompahgre, including $785,000 total grants from the Colorado Water Conservation Board.