Abstract Rationale α_v integrins, key regulators of transforming growth factor-β activation and fibrogenesis in in vivo models of pulmonary fibrosis, are expressed on abnormal epithelial cells (α_vβ₆) and fibroblasts (α_vβ₁) in fibrotic lungs. Objectives We evaluated multiple α_v integrin inhibition strategies to assess which most effectively reduced fibrogenesis in explanted lung tissue from patients with idiopathic pulmonary fibrosis. Methods Selective α_vβ₆ and α_vβ₁, dual α_vβ₆/α_vβ₁, and multi-α_v integrin inhibitors were characterized for potency, selectivity, and functional activity by ligand binding, cell adhesion, and transforming growth factor-β cell activation assays. Precision-cut lung slices generated from lung explants from patients with idiopathic pulmonary fibrosis or bleomycin-challenged mouse lungs were treated with integrin inhibitors or standard-of-care drugs (nintedanib or pirfenidone) and analyzed for changes in fibrotic gene expression or TGF-β signaling. Bleomycin-challenged mice treated with dual α_vβ₆/α_vβ₁ integrin inhibitor, PLN-74809, were assessed for changes in pulmonary collagen deposition and Smad3 phosphorylation. Measurements and main results Inhibition of integrins α_vβ₆ and α_vβ₁ was additive in reducing type I collagen gene expression in explanted lung tissue slices from patients with idiopathic pulmonary fibrosis. These data were replicated in fibrotic mouse lung tissue, with no added benefit observed from inhibition of additional α_v integrins. Antifibrotic efficacy of dual α_vβ₆/α_vβ₁ integrin inhibitor PLN-74809 was confirmed in vivo, where dose-dependent inhibition of pulmonary Smad3 phosphorylation and collagen deposition was observed. PLN-74809 also, more potently, reduced collagen gene expression in fibrotic human and mouse lung slices than clinically relevant concentrations of nintedanib or pirfenidone. Conclusions In the fibrotic lung, dual inhibition of integrins α_vβ₆ and α_vβ₁ offers the optimal approach for blocking fibrogenesis resulting from integrin-mediated activation of transforming growth factor-β.