Acute lung injury (ALI) is a common and severe respiratory disease with high morbidity and mortality. Although some progress has been made in the past years, the pathogenesis of ALI is still poorly understood and the therapeutic outcome has still not been significantly improved. It is well-recognized that magnesium sulfate (MgSO_4) possesses potent anti-inflammation capacity. The present study was designed to investigate the protective effects of MgSO_4 in lipopolysaccharides (LPSs)-induced ALI taken into account that excessive inflammatory response plays critical role in the development of ALI. In this study, Kunming mice were intravenously injected with LPS through tail vein to establish the ALI model and in parallel, A549 cells were used to establish cell model. The lung wet-to-dry weight ratio, malondialdehyde (MDA) levels in lung tissue, lung permeability index, hematoxylin and eosin staining, cytokines in the serum and bronchoalveolar lavage fluid (BALF), neutrophil counts in BALF, LPS-induced A549 cell apoptosis as well as apoptosis-inducing factor (AIF), and Poly(ADP-ribose) polymerase-1 (PARP-1) expression in both mice and A549 cells were detected. Our results demonstrated that MgSO_4 significantly attenuated the LPS-induced ALI, oxidative stress (decreased MDA levels), and lung inflammatory response. Moreover, MgSO_4 exerted protective effects by mitigating LPS-induced A549 cell apoptosis. Furthermore, MgSO_4 decreased the AIF and PARP-1 expression both in vivo and in vitro. Our results, taken together, demonstrated that MgSO_4 is a potential therapeutic agent for ALI taken into consideration that MgSO_4 is commonly used in clinical settings.