WIN 55212–2 is an endocannabinoids analogue that has been reported to have anti-inflammatory and anti-fibrosis effects on different models. In this study, we investigated the protective effects of WIN 55212–2 on paraquat (PQ)-induced poison on mice especially on lung injury. Mice were administrated with different dose of PQ and thereafter treated with 0.2 mg/kg or 1 mg/kg WIN 55212–2. The survival of mice was recorded during 4 weeks of observation. Twenty-eight days after PQ treatment, the cell population and inflammatory factors IL-6, IL-10, and TNF-α were measured in bronchoalveolar lavage fluid (BALF). Pulmonary fibrosis was evaluated by Masson staining. Our results showed that WIN 55212–2 treatment reduced PQ-induced mortality of mice in a dose dependent manner. It decreased the number of inflammation-associated cells, as well as the level of pro-inflammatory factors in BALF (P < 0.05). WIN 55212–2 increased M2 cells in BALF (P < 0.05), improved the lung histology, reduced fibrosis formation, and decreased TGF-β, α-SMA and PDGFRa expression. The protective effects of WIN 55212–2 on PQ-induced lung injury and fibrosis were associated with an increase inM2 cells and increased expressions of IL-10, CD163, and CD206, suggesting that polarization of M2 macrophages may be involved in WIN 55212–2 protective effects on PQ-induced lung injury.