Summary: Flow regulation and the effects of impoundment on water temperatures of the Lower Klamath River, California, have created favorable conditions for the myxosporean parasite Ceratonova Shasta, thereby causing recurring disease outbreaks in juvenile anadromous salmonids. To reduce mortality in juvenile salmon that pass through the “infectious zone”, an 80-km reach downstream of the lower-most impassable dam, resource managers hypothesized that bed scour from annual 3-day flushing flow events would reduce polychaete worm populations, the parasite’s intermediate host. To test this hypothesis, we incorporated a disease sub-model into the Stream Salmonid Simulator (S3), a spatially-explicit population model that simulates daily growth, movement, and mortality of juvenile Chinook Salmon in the Klamath River. We ran the model over a historic 12-year period that bracketed both high- and low-disease years and simulated flushing flow events to delay and reduce C. shasta spore densities. For all populations that passed through the infectious zone, annual flushing flows significantly reduced prevalence of infection and increased survival and the abundance of fish that entered the ocean. Our analysis shows how spatially-explicit models can help understand how management actions affect fish populations that migrate through spatially and temporally variable environments.