Water pollution poses a severe threat to global aquatic ecosystems, yet the adaptive mechanisms of aquatic organisms under such stress remain poorly understood. This study investigates the physiological and transcriptomic responses of the freshwater hydrozoan Craspedacusta sowerbii to two prevalent water pollutants: the antibiotic sulfamethoxazole (SMZ, 20 μM) and the heavy metal cadmium sulfate (Cd, 10 μM). Physiological observations revealed that SMZ exposure reduced motility and induced body shrinkage, while Cd exposure caused complete loss of motility, physical disintegration, and mortality within 24 hours. Transcriptomic analysis via RNA-seq identified significant alterations in gene expression patterns. SMZ exposure primarily up-regulated genes associated with oxidative stress, apoptosis, and immune responses, whereas Cd exposure resulted in extensive down-regulation of genes involved in metabolic pathways, cell cycle regulation, and anti-aging processes. Comparative analysis highlighted shared and distinct pathways affected by the two pollutants, including disrupted cell motility, cytokinesis, and molecular transducer activity. Notably, Cd exposure induced more severe transcriptional suppression, correlating with higher mortality. These findings underscore the ecological significance of C. sowerbii as a sensitive indicator of water quality and provide molecular insights into its adaptive strategies under pollution stress. Furthermore, the study offers critical implications for understanding the broader impacts of water pollutants on aquatic biodiversity, emphasizing the need for improved pollution control measures. Future research should focus on long-term multi-pollutant effects, field validation, and cross-species comparative studies to enhance ecological conservation strategies.