<p>Pharmaceuticals and Personal Care Products (PPCPs) are a distinct group of chemicals. Moreover, owing to PPCPs’ intrinsic capability of triggering different physiological effects in humans, they are particularly known as emerging environmental contaminants. The contamination due to these Emerging Contaminants (ECs) has gained extensive attention. Numerous studies have examined the contamination of PPCPs in rivers in the global context. Nevertheless, studies that specifically focus on the River Yamuna are still limited. Hence, the study aims to determine the occurrence, spatial dynamics, and risk assessment (RA) of PPCPs in the river Yamuna using a non-targeted Ultra-Performance Liquid Chromatography-Quadrupole Time-of-Flight Mass Spectrometry (UPLC-QTOF-MS) screening. Samples were collected from the six sites to conduct the study during the Post-Monsoon Season (PMS) and Pre-Monsoon Season (PRMS) in the years 2023—2024. Through the analysis, a total of 98 compounds are identified. By using Mixed Cation Exchange (MCX), Hydrophilic-Lipophilic Balance (HLB), and both MCX and HLB, 41, 29, and 28 compounds are identified, respectively. Among the identified compounds, most are hormones, steroids, and antibiotics. Many of the compounds are found in downstream locations. Subsequently, according to the RA, the risk level is extreme in downstream locations. High-risk and critical compounds are carcinogens, hormones and steroids, and antibiotics.</p> Graphical Abstract <p></p>