Anwulignan (AN) is a monomer lignan from Schisandra sphenanthera Rehd. et Wits (Schisandra sphenanthera fructus, Schisandra sphenanthera). The protective effect of AN against the indomethacin (IND)-induced gastric injury to mice and the related mechanism of action was investigated in this study. The effect of AN was mainly assessed by observing the gastric tissue morphology, gastric ulcer index (GUI), ulcer inhibition rate (UIR), gastric juice volume (GJV) and pH value. Chemical colorimetry, immunofluorescence, ELISA, and Western blot were used to detect related factors in the gastric tissue. The results showed that AN reduced the GUI, increased the UIR, inhibited the GJV, and increased the gastric pH value. AN significantly increased cyclooxygenase-1, cyclooxygenase-2, and prostaglandin E2 expression levels in the gastric tissue, activated nuclear factor (erythroid-derived 2)-like 2 (Nrf2), increased heme oxygenase-1 expression, enhanced the activity of superoxide dismutase and glutathione peroxidase, and decreased the malondialdehyde content. AN reduced the phosphorylation of nuclear factor-k gene binding (NF-kB) p65 and its nuclear translocation, the key protein of NF-kB signaling pathway in the gastric tissue, and the content of the pathway downstream signaling molecules, including interleukin-6, interleukin-1b, and tumor necrosis factor-a, to play an anti-inflammatory role. AN inhibited the downstream signals B-cell lymphoma 2associated x protein and cleaved caspase-3 in gastric tissue, and activated B-cell lymphoma 2, to play an antiapoptotic role, which were further verified by Hoechst staining. Therefore, AN has a significant protection against the gastric injury induced by IND in mice, and the mechanism may be concerned in its activation of Nrf2, inhibition of NF-kB signaling pathway, and antiapoptotic effect. SIGNIFICANCE STATEMENTAnwulignan (AN) significantly reduced the indomethacininduced gastric injury in mice, and its antioxidation, antiinflammation, and antiapoptosis were considered to be involve in the effect, suggesting that AN should be a potential drug or food supplement for gastric injury induced by indomethacin.