The details and mechanisms for Neogene river reorganization in the U.S. Pacific Northwest and northern Rocky Mountains have been debated for over a century with key implications for how tectonic and volcanic systems modulate topographic development. To evaluate paleo-drainage networks, we produced an expansive data set and provenance analysis of detrital zircon U-Pb ages from Miocene to Pleistocene fluvial strata along proposed proto-Snake and Columbia River pathways. Statistical comparisons of Miocene-Pliocene detrital zircon spectra do not support previously hypothesized drainage routes of the Snake River. We use detrital zircon unmixing models to test prior Snake River routes against a newly hypothesized route, in which the Snake River circumnavigated the northern Rocky Mountains and entered the Columbia Basin from the northeast prior to incision of Hells Canyon. Our proposed ancestral Snake River route best matches detrital zircon age spectra throughout the region. Furthermore, this northerly Snake River route satisfies and provides context for shifts in the sedimentology and fish faunal assemblages of the western Snake River Plain and Columbia Basin through Miocene−Pliocene time. We posit that eastward migration of the Yellowstone Hotspot and its effect on thermally induced buoyancy and topographic uplift, coupled with volcanic densification of the eastern Snake River Plain lithosphere, are the primary mechanisms for drainage reorganization and that the eastern and western Snake River Plain were isolated from one another until the early Pliocene. Following this basin integration, the substantial increase in drainage area to the western Snake River Plain likely overtopped a bedrock threshold that previously contained Lake Idaho, which led to incision of Hells Canyon and establishment of the modern Snake and Columbia River drainage network.