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Fine particulate matter (PM 2.5 ) is an air pollutant that causes severe lung injury. We investigated the effects of Jujuboside B (JB), a component of Zizyphi Spinosi Semen, on lung toxicity caused by PM 2.5 , and we identified the mechanism of its protective effect. Lung injury in an animal model was induced by intratracheal administration of a PM 2.5 suspension. After 2 days of PM 2.5 pretreatment, mice were administered JB via the tail vein three times over a 2-day period. JB significantly reduced the histological lung damage as well as the lung wet/dry weight ratio. JB also considerably reduced PM 2.5 -induced autophagy dysfunction, apoptosis, inflammatory cytokine levels, and the number of PM 2.5 -induced lymphocytes in the bronchial alveolar fluid. We conclude that by regulating TLR2, 4-MyD88, and mTOR-autophagy pathways, JB exerts a protective effect on lung injury. Thus, JB can be used as a potential therapeutic agent for PM 2.5 -induced lung damage.