The upregulation of TGF-β1 and integrin expression during wound healing has implicated these molecules in this process, but their precise regulation and roles remain unclear. Here we report that, notably, mice lacking β₃-integrins show enhanced wound healing with re-epithelialization complete several days earlier than in wild-type mice. We show that this effect is the result of an increase in TGF-β1 and enhanced dermal fibroblast infiltration into wounds of β₃-null mice. Specifically, β₃-integrin deficiency is associated with elevated TGF-β receptor I and receptor II expression, reduced Smad3 levels, sustained Smad2 and Smad4 nuclear localization and enhanced TGF-β1-mediated dermal fibroblast migration. These data indicate that α_vβ₃–integrin can suppress TGF-β1-mediated signaling, thereby controlling the rate of wound healing, and highlight a new mechanism for TGF-β1 regulation by β₃-integrins.