Pharmaceutical and microbial pollution in urban rivers is an emerging concern, particularly in developing regions with limited wastewater treatment capacity, posing risks to human health and ecosystems. This study evaluated the risk profiles of selected pharmaceutical compounds and bacterial indicators in the Sand River, South Africa, and computed their ecological risks, antimicrobial resistance (AMR), and human health risk assessment. Surface water samples were collected from three sites during the wet season and analyzed for target antibiotics and non-steroidal anti-inflammatory drugs (NSAIDs) using High-Performance Liquid Chromatography (HPLC) with a photodiode array (PDA) detector, while total coliforms (TCs) and Escherichia coli (E. coli) were enumerated using the Colilert system. Ciprofloxacin, sulfamethoxazole, and erythromycin were the most abundant pharmaceuticals, with maximum concentrations of 2.50 µg/L, 2.76 µg/L, and 2.53 µg/L, respectively. TC and E. coli levels exceeded regulatory thresholds, indicating severe microbial contamination. Risk quotient analysis identified ciprofloxacin, erythromycin, and trimethoprim as high-risk compounds for potential resistance selection (RQ ≥ 1), while ciprofloxacin and erythromycin posed significant ecological risks to fish. Although non-carcinogenic health risk assessment remained below concern (HI < 1), children showed higher exposure levels. These findings underscore the urgent need for improved pharmaceutical waste management and wastewater treatment infrastructure.