Objective The progression of pulmonary fibrosis is a common clinical issue after acute lung injury (ALI). We aimed to construct a model simulating clinical ALI-induced pulmonary fibrosis by repeated challenges with lipopolysaccharide (LPS). We then observed the development from ALI to pulmonary fibrosis, to explore the possible mechanisms mediating the transition from inflammatory injury to fibrosis. Methods Mice were treated with LPS (1, 2, 4, 8 mg/kg) intranasally to induce ALI. At 7 d, 14 d, 21 d, 28 d, 35 d, and 42 d after modeling respectively, α-smooth muscle actin (SMA), collagen 1 (Col-1), and hydroxyproline levels in lung tissue, and collagen fiber deposition were observed by Masson staining and compared to determine the process and degree of fibrosis formation in different modeling method. Expression changes in interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and transforming growth factor (TGF)-β1 in lung tissue at each time point were detected to explore the mechanisms of fibrosis formation. Results Treatment of mice with 1, 4, and 4 mg/kg LPS for 3 consecutive days (M-1 group) result ed in a stable ALI-induced pulmonary fibrosis model. Masson staining showed that α-SMA, Col1, hydroxyproline, and collagen fiber deposition in the lung tissue began to increase in M-1 group mice in a time dependent manner after 7 d. Collagen deposition in the lung tissue interstitium was significantly increased at 21 d post modeling, and fibrosis indicators were significantly increased at 28 d, compared with control mice. Collagen deposition continued to increase until 42 d. Hydroxyproline and collagen fibers in the lung tissue in the other model groups with different doses and hit times did not increase significantly compared with the control group. TGF-β1 expression detected by Western blot began to increase gradually 14 d after modelling in the M-1 group, and was significantly higher than in the control group at 28 d. The pro-inflammatory cytokines TNF-α and IL-1β increased significantly on day 7 (acute phase), and TNF-α expression continued to increase until 28 d, while IL-1β gradually decreased after day 7. TNF-α and IL-1β in the lung tissue both continued to decrease after the acute phase in the other model groups without fibrosis. Conclusions LPS 1, 4, and 4 mg/kg for 3 consecutive days can be used to construct an ALI/acute respiratory distress syndrome-induced pulmonary fibrosis model, via a mechanism that may be related to the sustained high expression of TNF-α regulating TGF-β1 to induce fibroblast activation and proliferation.