Acute lung injury (ALI) is a common disease characterized by pulmonary inflammation and oxidative stress. Sinomenine (SIN) is an alkaloid originally extracted from the Chinese medicinal plant Sinomenium acutum. It has been shown to have anti-inflammatory and anti-oxidative effect. However, it’s unclear whether SIN can alleviate ALI. In this study, we assessed the effect of SIN on Escherichia coli (E.coli)-induced ALI mouse model. Mice were conditioned with SIN or placebo 1 h before intratracheally instilled with E.coli. Lung water content, malondialdehyde (MDA) content, superoxide dismutase (SOD) activity, Myeloperoxidase (MPO) levels and inflammatory cytokines production were measured. Immunohistochemistry and western blot were performed to measure target protein expression. E.coli induced histological changes indicating tissues damage and increased W/D ratio, MPO activity, MDA content, and inflammatory cytokines production in the Lung. Whereas in mice pretreated with SIN, these changes were absent. E.coli-induced NF-κB activation was also inhibited by SIN. In addition, SIN increased the expression of HO-1, NQO1 and Nrf2 in lung tissues. Our results suggest that SIN attenuates ALI through the inhibition of inflammation and oxidative stress.