Here, we reported a novel nanotherapeutic platform for paraquat (PQ)-induced acute lung injury in animal models using simvastatin (SV) loaded into Poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NPs). In this way, Male Wistar rats orally received PQ (120 mg / kg) plus saline, SV (20 mg / kg) or PLGA-SV NPs containing 5, 10 and 20 mg SV/ kg. The levels of TNFα, IL-1β, IL-6 and glutathione content were evaluated. In addition, the pathological changes in the lung were monitored. Our results indicated that PQ (120 mg/kg) significantly reduced the body weight of rats compared to the control group. The most decrease in the level of inflammatory cytokines, bleeding, alveolar destruction as well as lymphocytic infiltration in the lung was observed at group treated with PLGA-SV NPs (10 mg). Free SV (20 mg) as well as PLGA-SV NPs (5 mg) modulated the inflammatory factors and glutathione content, however, they could not prevent tissue damage of PQ. Interestingly, PLGA-SV NPs (20 mg) could not improve the PQ- induced pulmonary damage. In conclusion, PLGA-SV NPs (10 mg) attenuated PQ-induced lung injury. The underlying mechanism may be relevant to increasing glutathione levels and inhibition of the production of inflammatory factors.