The occurrence of pharmaceutical residues in the aquatic ecosystem is an emerging concern of environmentalists. This study primarily investigated the seasonal variation of high-priority pharmaceutical residues in the Yamuna River, accompanied by 22 drains discharge from different parts of Delhi. Five sampling sites were selected for analyzing high-priority pharmaceuticals along with physico-chemical and biological parameters for 3 season's viz. pre-monsoon (PrM), monsoon (DuM), and post-monsoon (PoM), respectively. The maximum occurrences were detected during the PoM, compared to the PrM and DuM seasons. The maximum concentration of BOD, COD, and Phosphate was detected at the last sampling station (SP-5). Similarly, all targeted pharmaceuticals concentration were maximum at the last sampling point i.e. Okhla barrage (SP-5, max: DIC = 556.1 ng/l, IBU = 223.4 ng/l, CAR = 183.1 ng/l, DIA = 457.8 ng/l, OFL = 1726.5 ng/l, FRU = 312.2 ng/l and SIM = 414.9 ng/l) except at Barapulla downstream (SP-4, max: ERY = 178.1 ng/l). The mean concentrations of Fecal coliform (FC) ranged from 1700 to 6500 CFU/100 ml. The maximum colonies were detected in PrM season (6500 CFU/100 ml) followed by PoM (5800 CFU/100 ml) and least in DuM (1700 CFU/100 ml). Risk quotient (RQ) analysis of high-priority pharmaceuticals indicated high ecotoxicological risks exposure (>1) from DIC, DIA, OFL, and SIM in all seasons at all the sampling sites. However, lower risk was predicted for IBU, CAR, ERY, and FRU, respectively. This risk assessment indicated an aquatic ecosystem potentially exposed to high risks from these pharmaceutical residues. Moreover, seasonal agricultural application, rainfall, and temperature could influence the levels and compositions of pharmaceutical residue in the aquatic ecosystem. Hence, attention is required particularly to this stream since it is only a local lifeline source for urban consumers for domestic water supply and farmers for cultivation.