Rivers are a means of rapid and long-distance transmission of pathogenic microorganisms from upstream terrestrial sources. Pathogens enter streams and rivers via overland flow, shallow groundwater discharge, and direct inputs. Of concern is the protozoal parasite, Cryptosporidium, which can remain infective for weeks to months under cool and moist conditions, with the infectious stage (oocysts) largely resistant to chlorination. We applied a mobile-immobile model framework to assess Cryptosporidium transport and retention in streams, that also accounts for inactivation. The model is applied to California’s Central Valley where Cryptosporidium exposure can be at higher risk due to agricultural and wildlife nonpoint sources. The results demonstrate that hyporheic exchange is an important process to include in models characterizing pathogen dynamics in streams, delaying downstream transmission and allowing for immobilization processes, such as reversible filtration in the sediments, to occur. Although in-stream concentrations decrease relatively quickly (within hours), pathogen accumulation of up to 66% of the inputs due to immobilization processes in the sediments and slower moving surface water could result in long retention times (months to years). The model appropriately estimates baseflow pathogen accumulation and can help predict the potential loads of resuspended pathogens in response to a storm event.