The sixth UN Sustainable Development Goal, Clean Water and Sanitation, directly underpins other goals of Health, Life in Water and Sustainable Cities. We highlight that poor sanitation, exemplified through some of the highest concentrations of pharmaceuticals ever detected in rivers, will amplify societal and environmental stress where climate-induced reductions in flow are predicted. Rapidly growing urban centres with inadequate water treatment works will need to prioritise water quality improvement before supply reductions become a reality. For 23 river locations within Kathmandu City and the Annapurna region, Nepal, we show the presence of 28 of 35 monitored human-use pharmaceuticals. Concentrations of antibiotics measured in this sampling campaign in both Kathmandu City (sulfamethazine, metronidazole and ciprofloxacin) and rural locations (ciprofloxacin) are in excess of predicted no effect concentrations, suggesting these sites are at risk of proliferating antimicrobial resistance as well as affecting other ecotoxicological endpoints. It is anticipated that climate-induced reductions in flow combined with contaminated river systems will amplify future societal and environmental stress.