Rheumatoid arthritis (RA) is a systemic inflammatory and autoimmune disease. In this research, we estimated the protective effects of Dihydromyricetin (DMY) on RA induced by Complete Freund's Adjuvant (CFA). We found that DMY effectively relieved rheumatoid arthritis symptoms, such as body weight change, paw swelling and rheumatoid arthritis scores. In addition, we also observed that DMY significantly lowered the immune organ indexes (including thymus and spleen) and exhibited the anti-inflammatory effect in CFA-induced rheumatoid arthritis. The results demonstrated that the increased expression levels of interleukin-1β (IL-1β), interleukin-6(IL-6), tumor necrosis factor-α (TNF-α) were significantly inhibited by DMY. Furthermore, the key inflammatory mediator, cyclooxygenase-2 (COX-2) was markedly lowered after treatment with DMY. A mechanistic study indicated that DMY could up-regulate the down-regulation levels of the mRNA and protein of Nrf2, HO-1 and NQO1. Moreover, the Nrf2 activation of DMY was abolished by Nrf2 inhibitor brusatol. Thus, DMY inhibits the expressions of pro-inflammatory cytokines via activating Nrf2 pathway in RA model, which suggests that DMY has potential for further investigation as a candidate anti-arthritic agent in future.