In the context of global climate change, the increasing frequency of droughts in Alpine streams represents a recent and underexplored phenomenon. This study adopts a multidisciplinary approach to investigate the response of three Alpine rivers in Northwestern Italy to severe hydrological stress during an exceptionally dry year (2022). While climate change is often framed in terms of water quantity, its consequences on water quality especially when coupled with local pressures such as wastewater discharge remain poorly understood. In this study we focused on the impact of three wastewater treatment plants (WWTPs), analysing monthly variations in hydrological, chemical, microbiological, and ecological parameters along upstream (U) and downstream (D) river stretches. The study encompassed not only traditional metrics such as nutrient load, microbial contamination, and biodiversity indices (diatoms and macroinvertebrates), but also included a path analysis to quantify the interconnections among microbiological, chemical, and biological responses to flow reduction. Our results show that decreased flow significantly amplifies the impact of WWTP discharges. At very low flow conditions, downstream reaches exhibit biodiversity loss, increased presence of pollution-tolerant taxa, chemical degradation, and the spread of pathogenic microbial strains. These findings suggest a systemic collapse in both ecosystem integrity and potential sanitary safety. To synthesise the complex interplay of stressors, we calculated an index inspired by the One Health approach that integrates hydrological, ecological, chemical, and microbiological data. This index highlights how drought and anthropogenic pressures jointly undermine river health, reinforcing the deep interconnection between environmental degradation and human well-being. Given the projected intensification of drought events across Europe, our study can serve as a first building block and provide a useful starting point for future research aimed at improving our understanding of some of the largely overlooked consequences of these events.