The present study aimed to investigate the occurrence of caffeine residues in the Nile River according to drainage of treated wastewater at Assiut, Egypt, and the effects of physicochemical parameters and zinc on its concentration. Four different sites were selected to perform the study: S, wastewater treatment plant (WWTP) canal (source site); J, a junction site between WWTP canal and the Nile; R, a reference site in the Nile before J site; and A, a site located after J site in the Nile. Water and sediment samples were collected in Summer 2022 and Winter 2023. Caffeine and Zn concentrations and physicochemical parameters were measured in the collected samples. The caffeine concentrations in water samples ranged from 5.73 to 53.85 μg L−1 at S in winter and summer, respectively, while those in sediment ranged from 0.14 mg kg−1 at R in winter to 1.54 mg kg−1 at S in summer. Caffeine and Zn concentrations were higher in summer samples. The Water Quality Index (WQI) of the collected samples recorded the lowest values in winter season at S and J sites. The study found that caffeine and zinc concentrations are positively correlated with water temperature and conductivity, while negatively correlated with pH. The association between caffeine and Zn highlights the environmental impact of heavy metals and pharmaceutical residues, and stresses the need for future research on these interactions.