The proinflammatory factor high?mobility group box protein 1 (HMGB1) has been implicated in the pathogenesis of lung fibrosis; however， the role of HMGB1 in lung fibrosis remains unclear. It has previously been reported that nuclear factor (NF)?κB and transforming growth factor (TGF)?β1 may be involved in lung fibrosis. Therefore， the present study aimed to examine the potential molecular mechanisms that underlie HMGB1?induced lung fibrosis via the regulation of NF?κB and TGF?β1. The results demonstrated that HMGB1 stimulation increased the activation of NF?κB and the release of TGF?β1， as well as the expression of α?smooth muscle actin (α?SMA) and collagen I in human lung fibroblasts in?vitro. In addition， inhibition of NF?κB activation blocked HMGB1?induced TGF?β1 release， as well as α?SMA and collagen I expression in lung fibroblasts. Preventing the release of TGF?β1 inhibited HMGB1?induced α?SMA and collagen I expression; however， it had no effect on NF?κB activation. Collectively， these findings indicate that HMGB1 induces fibroblast to myofibroblast differentiation of lung fibroblasts via NF?κB?mediated TGF?β1 release.