Objective To investigate the impact of ephedrine on knee osteoarthritis (KOA) in rats by regulating AMPK/NF-κB signaling pathway. Methods KOA rat models were established and grouped into Sham group, KOA group, Ephedrine group (40.0mg/kg), and Ephedrine group (40.0mg/kg)+Compound C group (0.2mg/kg). After drug grouping intervention, the knee joint width and pain threshold of rats were measured respectively,the pathological changes of cartilage tissue were observed with safranine O-solid green staining and Mankin score was performed,the levels of TNF-α, IL-1β and COX-2 in synovial fluid were detected by ELISA,the expression of IL-1β and MMP-13 proteins in cartilage tissue was detected by immunohistochemistry,Western blot was applied to detect the level of AMPK/NF-κB pathway related proteins. Results Compared with Sham group, the cartilage tissue of KOA group was seriously damaged,the knee joint width, Mankin score, levels of TNF-α, IL-1β, COX-2 in joint fluid, and levels of IL-1β, MMP-13, and p-NF-κB p65/NF-κB p65 in cartilage tissue were significantly higher, and the pain threshold and the level of p-AMPK/AMPK in cartilage tissue were significantly lower (P<0.05);compared with KOA group, the pathological damage of cartilage tissue in Ephedrine group was reduced,the knee joint width, Mankin score, levels of TNF-α, IL-1β, COX-2 in joint fluid, and levels of IL-1β, MMP-13, and p-NF-κB p65/NF-κB p65 in cartilage tissue were significantly lower, and the pain threshold and the level of p-AMPK/AMPK in cartilage tissue were significantly higher (P<0.05); compared with the Ephedrine group, the injury of cartilage tissue in the Ephedrine+Compound C group was aggravated,the knee joint width, Mankin score, levels of TNF-α, IL-1β, COX-2 in joint fluid, and levels of IL-1β, MMP-13, and p-NF-κB p65/NF-κB p65 in cartilage tissue were significantly higher, and the pain threshold and the level of p-AMPK/AMPK in cartilage tissue were significantly lower (P<0.05). Conclusion Ephedrine can inhibit NF-κB signal pathway, inhibit inflammatory reaction and improve cartilage injury in KOA rats by activating AMPK pathway. [ABSTRACT FROM AUTHOR]