Multi-drug resistant microbes, pathogenic viruses, metals, and pharmaceuticals and personal care products (PPCPs) in water has become the crux of urban sustainability issues. However, vulnerability due to pollutant concurrences, source apportionment, and identification of better faecal indicators needs to be better understood. The present study focuses on the vulnerability of urban Guwahati, the largest city in Northeastern India, through analyzing the concurrence of PPCPs, enteric viruses, antibiotic resistant bacteria, metal, and faecal contamination in water. The study strives to identify a relevant marker of anthropogenic pollution for the Indian scenario. Samples from the Brahmaputra River (n = 4), tributary Bharalu River (an unlined urban drain; n = 3), and Ramsar recognized Lake (Dipor Bil; n = 1) indicate caffeine > acetaminophen > theophylline > carbamazepine > crotamiton for PPCPs and pepper mild mottle virus (PMMoV) > aichi > hepatitis A > norovirus GII > norovirus GI for enteric viruses. PMMoV was the better indicator of faecal pollution due to its prevalence, specificity and ease of detection. Antibiotic resistance was neither correlated with the prevalence of PPCPs nor E. coli. As, Co and Mn appear to be inducing antibiotic resistance in E. coli. While the risk quotient of the urban drain (Bharalu River) indicates one order higher magnitude than reported for other Indian rivers, the Lake exhibited the least pollution and better resilience. The concurrence of pollutants and multi-drug resistant E. coli, owing to the complete absence of wastewater treatment, puts the city in a highly vulnerable state. Pollution is being regulated only by the dilution capability of the Brahmaputra River, which needs to be further researched for seasonal variation.