Pulmonary fibrosis (PF) has limited therapeutic options because its molecular pathogenesis remains unclear. Chemokine (C-C motif) ligand 20 (CCL20) plays crucial roles in the pathogenesis of various immune diseases. However, its role in PF is unknown. Here, we showed that CCL20 expression was significantly increased in the lung tissues of PF mouse models and PF patients compared with healthy controls. 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 reduced established PF. Overall, our study highlights the CCL20-integrin α5β1-TGF-β signaling cascade as a potential therapeutic target for PF.