PURPOSE: Apigenin, a flavonoid found in edible plants, has demonstrated therapeutic potential in various diseases, but its role in knee osteoarthritis (KOA) remains unclear. This study aimed to identify the potential targets and mechanisms of Apigenin in KOA. METHODS: Network pharmacology analysis identified 80 targets of Apigenin, of which 48 overlapped with KOA-related targets. Summary-data-based Mendelian randomization (SMR) analysis and molecular docking were utilized to explore key target genes. Single-cell RNA sequencing data from human cartilage tissue and in vitro studies using SW1353 cells treated with 3 % hydrogen peroxide (H2O2) were analyzed to validate findings. RESULTS: SMR analysis identified EIF6 as a potential target of Apigenin in KOA, negatively associated with disease progression. Molecular docking revealed strong binding affinity between Apigenin and EIF6. Single-cell analysis suggested downregulation of EIF6 may contribute to chondrocyte senescence. In vitro, Apigenin (20 μM) reversed H2O2-induced senescence and increased EIF6 expression in SW1353 cells, improving cell viability. CONCLUSION: Apigenin upregulates EIF6 expression and mitigates H2O2-induced chondrocyte senescence, highlighting its potential as a therapeutic agent for KOA. These findings provide insights into the nutritional health benefits of Apigenin and its implications for KOA treatment.