Anwulignan is one of the monomer compounds in the lignans from Schisandra sphenanthera In this study, we observed the effect of anwulignan on intestinal ischemia/reperfusion (II/R) injury in male Sprague-Dawley rats and explored the underlying mechanisms. The results showed that pretreatment with oral anwulignan could significantly increase the mesenteric blood microcirculatory flow velocity; relieve the congestion and pathologic injury of jejunum; enhance the autonomic tension of jejunum smooth muscle and its reactivity to acetylcholine; increase the activities of superoxide dismutase, catalase, glutathione S-transferase, and choline acetyltransferase; increase the contents of acetylcholine and glutathione in the serum or jejunal tissue; decrease the activities of myeloperoxidase, protein kinase C, and nicotinamide adenine dinucleotide phosphate oxidase; reduce the contents of malondialdehyde, 8-hydroxy-2-deoxyguanosine, nicotinamide adenine, reactive oxygen species, tumor necrosis factor-α, interleukin (IL)-6, and IL-1β; increase the expression levels of muscarinic receptor 3, PI3K, phosphorylation protein kinase B, p-GSK3β Ser9, Nrf2, p-Nrf2, heme oxygenase (decycling) 1, and b-cell lymphoma 2 in the jejunal tissue; and decrease the expression levels of p-GSK3β Tyr216, kelch-like ECH-associated protein 1, Bax, and cleaved caspase-3, suggesting that anwulignan can ameliorate II/R-induced jejunal tissue injury in rats and that the mechanism may be related to its activating the PI3K/protein kinase B pathway and then regulating the Nrf2/Anti-oxidative Response Element signaling pathway and the expression of apoptosis-related proteins to play antioxidant and antiapoptotic roles. SIGNIFICANCE STATEMENT: Anwulignan can significantly reduce jejunal tissue injury and the production of inflammatory factors in rats with intestinal ischemia-reperfusion injury, improve the antioxidant capacity, and reduce the apoptosis of jejunal tissue, and it has the effect of significantly improving intestinal ischemia-reperfusion injury in rats, suggesting that anwulignan may be used as a potential drug for the prevention and treatment of intestinal ischemia-reperfusion injury or a resource for the development of health food.