River Yamuna is one of the major lifelines of Northern India. The study quantified 16 target compounds including pharmaceuticals, personal care products, and hormones in the Yamuna river. Surface water samples were collected from 13 locations spanning 575 km along the river, and from two of its tributaries, Hindon river and Hindon canal. Spatiotemporal variations in the occurrence of the target compounds at the 13 sites during summer and post-monsoon season were investigated. Caffeine, estrone, gemfibrozil, sulfamethoxazole, testosterone and trimethoprim were found in all the samples, indicating substantial usage and/or persistence in the environment. The mean concentration of the target compounds ranged from 25.5 to 2187.5 ng/L. Higher concentrations were detected during the post monsoon, compared to the summer season. The highest concentration detected was of trimethoprim (8807.6 ng/L) during summer sampling, followed by caffeine (6489.9 ng/L) and gemfibrozil (2991 ng/L), during the post-monsoon sampling. The lowest concentration detected was of estrone (10.7 ng/L), during the summer sampling. The runoff from the catchment areas is one of the contributing factors for the increased concentration of the compounds during post monsoon. During summer, the river bed goes dry, facilitating the adsorption of the compounds onto the river bed sediments. The three sampling locations Okhla barrage (ponding of water from drains traversing Delhi), confluence of Yamuna with Shahadara drain (industrial and poultry cluster, and Ghazipur dumping yard) and Agra city (industrial clusters) were the hotspots in terms of total concentration of the target compounds. The study also reported the presence of PPCPs and hormones in the finished drinking water of two DWTPs at Mathura and Agra.