Microbial pollution is a major problem worldwide. High concentrations of Escherichia coli have been found in Kabul River in Pakistan. E. coli concentrations vary under different socio-economic conditions, such as population and livestock densities, urbanisation, sanitation and treatment of wastewater and manure, and climate-change aspects, such as floods and droughts. In this paper, we assess potential future E. coli loads and concentrations in the Kabul River using the Soil and Water Assessment Tool with scenarios that are based on the most recent Shared Socio-economic Pathways and Representative Concentration Pathways (SSPs and RCPs) developed for the Intergovernmental Panel on Climate Change (IPCC). Scenario_1 considers moderate population and livestock density growth, planned urbanisation and strongly improved wastewater and manure treatment (based on SSP1, “Sustainability”), and moderate climate change (RCP4.5, moderate greenhouse gas (GHG) emissions). Scenario_2 considers strong population and livestock density growth, moderate urbanisation, slightly improved wastewater treatment, no manure treatment (based on SSP3, “Regional rivalry”) and strong climate change (RCP8.5, high GHG emissions). Simulated E. coli responses to Scenario_2 suggest a mid-century increase in loads by 111% and a late century increase of 201% compared to baseline loads. Similarly, simulated E. coli loads are reduced by 60% for the mid-century and 78% for the late century compared to the baseline loads. When additional treatment is simulated in Scenario_1, the loads are reduced even further by 94%, 92% and 99.3% compared to the baseline concentrations when additional tertiary treatment, manure treatment or both have been applied respectively. This study is one of the first to apply combined socio-economic development and climate change scenario analysis with an E. coli concentration model to better understand how these concentrations may change in the future. The scenario analysis shows that reducing E. coli concentrations in Pakistan's rivers is possible, but requires strongly improved waste water treatment and manure management measures.