Abstract: Objective: To investigate the protective effects of Armillaria mellea polysaccharides on lung injury induced by nicotine in rats. Methods: SD rats were randomly divided into control group, model group and Armillaria mellea polysaccharides low and high dose groups. During modeling, except for the normal group, the other groups were intraperitoneally injected with nicotine 2 mg/kg body weight, and the low and high dose groups were gavaged with Armillaria mellea polysaccharides 200 and 400 mg/kg body weight, respectively. The morphologic changes of lung tissue were observed by HE staining. The levels of TNF-α, IL-6 and IL-1β were detected by ELISA, MDA level was detected by TBA method, SOD activity was detected by WST-1 method. The protein expression levels of Nrf2, HO-1 and p-NF-κB in lung tissues were detected by Western blot assay. Results: Compared with the control group, after intervention of nicotine, the levels of TNF-α, IL-6, IL-1β and MDA were increased, the activity of SOD was decreased in plasma, the phosphorylation expression of NF-κB protein was increased, Nrf2 and HO-1 protein expression were decreased in lung tissue. Compared with the model group, after intervention of Armillaria mellea polysaccharides, the degree of lung tissue injury was alleviated, the levels of TNF-α, IL-6, IL-1β and MDA were significantly decreased, the activity of SOD was increased in plasma, the phosphorylation expression of NF-κB protein was significantly decreased, Nrf2 and HO-1 protein expression were significantly increased in lung tissue. Conclusion: Armillaria mellea polysaccharides could inhibit the lung tissue injury by nicotine induced. The mechanism of action may be related to its regulation of NF-κB and Nrf2/HO-1 signaling pathway.