Background Extracellular matrix (ECM) degradation, chondrocyte inflammation, and cellular senescence contribute to the pathology of osteoarthritis (OA). Empagliflozin, a selective inhibitor of sodium-glucose cotransporter-2 (SGLT2), has been reported to show the anti-inflammatory properties in several conditions. However, whether empagliflozin can be used to improve OA is still unknown. Methods The protective effects and underlying mechanism of empagliflozin in OA were investigated in vitro and in vivo. Cell viability, catabolic markers, inflammatory mediators, cellular senescence level, cartilage degeneration were evaluated by CCK-8 assay, safranine O staining, ELISA, real-time PCR, western blot, β-galactosidase Staining, and histological analysis. Results We found that empagliflozin significantly downregulated the expression of catabolic enzymes (MMP9 and MMP13), and decreased the expression of inflammatory mediators (NO, PGE2, IL-6, COX2, and INOS), and reduced the cellular senescence level in IL-1β-treated chondrocytes by inhibiting the nuclear factor kappa-B (NF-κB) signaling pathway. What’s more, empagliflozin prevented cartilage degeneration in DMM-induced OA mice model with significant lower OARSI grade. Conclusion Our findings reveal that empagliflozin inhibited chondrocytes ECM degradation, inflammation and cellular senescence in vitro and prevented cartilage degeneration in vivo by suppressing NF-κB signal pathway, indicating a therapeutic potential in OA treatment.