Osteoarthritis (OA), a progressive joint disorder, is principally characterized by the degeneration and destruction of the articular cartilage. Ellagic acid (EA), a natural polyphenol found in berries and nuts has shown potent anti-inflammatory effects, however, its effects and underlying mechanisms on OA have seldom been systematically illuminated. In this study, we reported the anti-inflammatory effects of Ellagic acid (EA) in the progression of OA in both in vitro and in vivo experiments. in vitro study, IL-1β-induced expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), Nitric oxide (NO), tumor necrosis factor-alpha (TNF-α), prostaglandin E2 (PGE2), and interleukin-6 (IL-6) were inhibited by Ellagic acid (EA). Moreover, Ellagic acid (EA) down-regulated the IL-1β-stimulated matrix metalloproteinase-13 (MMP-13) and thrombospondin motifs 5 (ADAMTS-5) while up-regulated the collagen of type II and aggrecan. Mechanistically, we revealed that Ellagic acid (EA) suppressed nuclear factor kappa B (NF-κB) signaling in IL-1β -induced chondrocytes. And Ellagic acid (EA)-induced protectiveness in OA development was also shown by the DMM model. Taken together, our data indicate that Ellagic acid (EA) may serve as a potential drug for OA treatment.