Limited therapeutic options are available for pulmonary fibrosis (PF) because its molecular pathogenesis remains unclear. Here, we found that chemokine (C-C motif) ligand 20 (CCL20) expression was increased in murine PF models and PF patients. Type 2 alveolar epithelial cells (AEC2s) were identified as the major producers of CCL20, and increased CCL20 expression resulted from decreased expression of the transcription factor JUN. AEC2-specific deletion of CCL20 protected mice from bleomycin (BLM)-induced PF. Mechanistic studies revealed that CCL20 interacted with integrin α5β1, but not the classical receptor CCR6, on fibroblasts and subsequently enhanced transforming growth factor-β (TGF-β)/Smad signaling, which promoted the differentiation of lung fibroblasts into myofibroblasts. Antibody blockade of CCL20 or disruption of the CCL20–integrin α5β1 interaction attenuated established PF. Overall, our study highlights the CCL20–integrin α5β1–TGF-β signaling cascade as a potential therapeutic target for PF.