Summary Little is known about microbial communities in the Ganges River, India and how they respond to intensive anthropogenic inputs. Here we applied shotgun metagenomics sequencing to study microbial community dynamics and function in planktonic samples collected along an approximately 700 km river transect, including urban cities and rural settings in upstream waters, before and after the monsoon rainy season. Our results showed that 11%–32% of the microbes represented terrestrial, sewage and human inputs (allochthonous). Sewage inputs significantly contributed to the higher abundance, by 13‐fold of human gut microbiome (HG) associated sequences and 2‐fold of antibiotic resistance genes (ARGs) in the Ganges relative to other riverine ecosystems in Europe, North and South America. Metagenome‐assembled genome sequences (MAGs) representing allochthonous populations were detectable and tractable across the river after 1–2 days of (downstream) transport (> 200 km apart). Only approximately 8% of these MAGs were abundant in U.S. freshwater ecosystems, revealing distinct biodiversity for the Ganges. Microbial communities in the rainy season exhibited increased alpha‐diversity and spatial heterogeneity and showed significantly weaker distance‐decay patterns compared with the dry season. These results advance our understanding of the Ganges microbial communities and how they respond to anthropogenic pollution.