Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a common clinical syndrome of diffuse lung inflammation with high mortality rates and limited therapeutic methods. Diosmetin, an active component from Chinese herbs, has long been noticed because of its antioxidant and anti-inflammatory activities. The aim of this study was to evaluate the effects of diosmetin on LPS-induced ALI model and unveil the possible mechanisms. Our results revealed that pretreatment with diosmetin effectively alleviated lung histopathological changes, which were further evaluated by lung injury scores. Diosmetin also decreased lung wet/dry ratios, as well as total protein levels, inflammatory cell infiltration and proinflammatory cytokine (eg. TNF-α, IL-1β and IL-6) overproduction in bronchoalveolar lavage fluid (BALF). Additionally, increased MPO, MDA and ROS levels induced by LPS were also markly suppressed by diosmetin. Furthermore, diosmetin significantly increased the expression of Nrf2 along with its target gene HO-1 and blocked the activation of NLRP3 inflammasome in the lung tissues, which might be central to the protective effects of diosmetin. Further supporting these results, in vitro experiments also showed that diosmetin activated Nrf2 and HO-1, as well as inhibited the NLRP3 inflammasome in both RAW264.7 and A549 cells. The present study highlights the protective effects of diosmetin on LPS-induced ALI via activation of Nrf2 and inhibition of NLRP3 inflammasome, bringing up the hope of its application as a therapeutic drug towards LPS-induced ALI.