Objective To investigate the ameliorative effects and preliminary mechanism of polydatin on sulfur mustard (SM)-induced lung injuries. Methods In the survival experiment, male ICR mice were randomly divided into 6 groups (n=15):control group; SM group (40 mg/kg); low-, medium- and high-does polydatin groups (100, 200 and 400 mg/kg daily for 7 d, respectively); and positive control group (200 mg/kg N-acetyl-L-cysteine daily for 7 d). In other experiments, mice were randomly divided into 4 groups (n=15):control group, SM group (30 mg/kg), medium-dose polydatin group (200 mg/kg daily for 5 d) and positive control group (200 mg/kg N-acetyl-L-cysteine daily for 5 d). The mouse model of SM-induced lung injuries was established by subcutaneous injection of SM solution. The polydatin group and positive control group were given drugs by gavage. The survival experiment was used to preliminarily investigate the effects of polydatin on SM-induced lung injuries and to determine the best dose of polydatin. The ameliorative effect of polydatin on SM-induced lung injuries was evaluated by lung tissue sections. The levels of oxidative stress indexes such as superoxide dismutase (SOD), glutathione (GSH), myeloperoxidase (MPO), malondialdehyde (MDA) and hydrogen peroxide and inflammatory response indexes such as interleukin (IL)-1β, IL-6 and tumor necrosis factor α (TNF-α) were detected by enzyme-linked immunosorbent assay. The expression levels of key proteins of oxidative stress such as silencing information regulator 1 (SIRT1), nuclear factor E2-related factor 2 (Nrf2), heme oxygenase 1 (HO-1), NAD(P)H:quinone oxidoreductase 1 (NQO1), as well as the levels of key inflammatory proteins such as Toll-like receptor 4 (TLR4) and nuclear factor κB (NF-κB) p65 were detected by Western blotting. Results Compared with the SM group, the survival rates of mice were increased in the medium- and high-does polydatin groups, and the effect of the medium-dose polydatin group was more significant (P<0.01). Intervention with medium-dose polydatin could increase SOD activity and GSH content in the lung tissues of SM-exposed mice, and reduce MPO activity, contents of MDA and hydrogen peroxide, and the levels of inflammatory cytokines such as IL-1β, IL-6 and TNF-α (P<0.05 or P<0.01); enhance the protein expression of SIRT1 in lung tissues of SM-exposed mice, promote nuclear metastasis of Nrf2, and enhance the protein expression of HO-1 and NQO1 (P<0.05 or P<0.01); and decrease the protein expression of TLR4, NF-κB p65 and phosphorylated NF-κB p65 in lung tissues (P<0.01). Conclusion Polydatin may inhibit SM-induced oxidative stress and inflammatory response by regulating SIRT1/Nrf2 and TLR4/NF-κB pathways, so as to ameliorate the SM-induced lung injuries in mice.