Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease and characterized by abnormal growth of fibroblasts and lung scarring. While the pathogenesis of IPF is not clearly understood, activation of transforming growth factor-β (TGF-β) and disruption of alveolar basement membrane seem to play important roles in leading to excess disruption of the matrix, which is associated with activated matrix metalloproteinase (MMP) and aberrant proliferation of myofibroblasts. The Wnt/β-catenin pathway is an important regulator of cellular proliferation and differentiation and abnormal activation of Wnt/β-catenin signal was observed in IPF. We examined whether inhibition of the Wnt/β-catenin pathway could attenuate pulmonary fibrosis in a bleomycin-induced murine model of pulmonary fibrosis. Pulmonary fibrosis was induced in C57BL/6N mice by intratracheal instillation of bleomycin. To inhibit the Wnt/β-catenin pathway, small interfering RNA (siRNA) for β-catenin was administered into trachea 2 h before bleomycin instillation and every 48 h afterward until sacrifice on day 14. The level of β-catenin expression was increased in the epithelial cells of bleomycin-administered mice. Intratracheal treatment with β-catenin siRNA significantly reduced β-catenin expression, pulmonary fibrosis and collagen synthesis in bleomycin-administered mice compared with controls, with no significant effect on the inflammatory response. The β-catenin-targeted siRNA also significantly decreased the levels of MMP-2 (P<0.01) and TGF-β (P<0.01) expression in the lung tissue. Blockade of the Wnt/β-catenin pathway by β-catenin siRNA decreased bleomycin-induced pulmonary fibrosis in the murine model. These findings suggest that targeting Wnt/β-catenin signaling may be an effective therapeutic approach in the treatment of IPF.