Currently, limited research exists on the relationship between osteoarthritis (OA) and Benzophenone-3 (BP-3). This study aims to explore the potential molecular pathways involved, using both in vivo and in vitro biological experiments. In vivo experiments revealed that exposure to BP-3 leads to cartilage damage in the knee joints of rats, suggesting that BP-3 may be a significant risk factor in the development and progression of osteoarthritis. Proteomic sequencing of knee cartilage tissue revealed alterations in multiple inflammatory pathways in the BP-3 group. In vitro cellular experiments further demonstrated the toxic effects of BP-3 on chondrocytes, including inflammatory changes and increased transcriptional levels of IL-6. Cellular transcriptomics sequencing revealed significant changes in multiple intracellular inflammatory pathways, particularly the JAK-STAT pathway. Additional experiments demonstrated that BP-3 enhances STAT3 phosphorylation, promoting the degradation of extracellular matrix (ECM) proteins. Silence of STAT3 alleviated the impaired effects of BP-3 on chondrocytes. Overall, our data suggest that BP-3 exposure may be a significant risk factor for OA development. This study provides substantial evidence and a comprehensive understanding of the impact of BP-3 on OA development.