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Recent evidence indicates that the antimalarial agent artesunate (ART) has immunomodulatory properties that may be useful for treating rheumatoid arthritis (RA). However, the effects of ART on the RA animal model have not been described. The current study aimed to evaluate the antiarthritic effect of ART and explore the potential mechanism on type II collagen-induced arthritis (CIA) in rats. From the day of arthritis onset, rats were treated daily by gavage with leflunomide (Lef) or ART at a dosage of 10 mg/kg/d or 5 mg/kg/d, respectively, for 16 days. The severity of arthritis and levels of pro- and anti-inflammatory cytokines in site were measured. The expression and activity of metalloproteinase (MMP)-2 and MMP-9 were determined. The activation of nuclear factor kappa B and mitogen-activated protein kinase signaling pathways was investigated in rats with CIA and in Raw264.7 cells. Our results showed that ART treatment significantly attenuated inflammation symptoms and prevented cartilage and bone destruction. ART decreased expression of the proinflammatory cytokines interleukin-1β, tumor necrosis factor-α, and interleukin-17α. Both expression and activity of MMP-9 were efficiently inhibited by ART. ART significantly inhibited the degradation of IκB and activation of extracellular signal-regulated kinase and c-Jun N-terminal kinase in rats with CIA and in lipopolysaccharide-stimulated Raw264.7 cells. The present study demonstrated that ART ameliorated rat CIA. The antiarthritic effect might be achieved by inhibiting the action of proinflammatory cytokines and the activity of MMP-9 via suppression of nuclear factor kappa B and mitogen-activated protein kinase signaling pathway. These results show that ART may be used as an adjuvant therapy for patients with RA.