The impact of waterborne micro-organisms (potentially pathogenic) on public health may be exacerbated by the combined effects of climate and land use change. We used watershed modeling to assess the potential effects of climate change and future land management scenarios on microbial water quality in the Pigg River watershed, located in southwest Virginia, USA. The hydrologic simulation program in Fortran, climate forecasts from the Consortium for Atlantic Regional Assessment, future projections for land management, and current watershed data were used to simulate a range of potential future scenarios for the period 2040–2069. Results indicate that changes in climate will have the most significant impact on microbial fate and transport, with increased loading driven by trends in seasonal and annual precipitation. High flow and low flow periods represent periods of greatest uncertainty. As climate factors are to an extent uncontrollable, adaptation measures targeting land based source loads will be required to maintain water quality within existing regulatory standards. In addition, new initiatives may need to be identified and incorporated into water policy. This is likely to have repercussions for all watershed inhabitants and stakeholders, but will assist in sustaining water quality standards and protecting human health.