The differentiation of atrial fibroblasts into myofibroblasts is a critical event in atrial fibrosis. One of the most important factors in atrial fibroblast differentiation is transforming growth factor-beta 1 (TGF-beta 1). Accumulating evidence indicates that sodium tanshinone IIA sulfonate (STS) possesses antifibrotic properties. In this study, we therefore investigated whether STS attenuates the TGF-beta 1-induced differentiation of atrial fibroblasts. TGF-beta 1 enhanced collagen production, collagen synthesis and the expression of collagen type I and III, as shown by hydroxyproline assay, collagen synthesis assay and western blot analysis, respectively. In addition, as shown by immunohistochemistry and western blot analysis, TGF-beta 1 enhanced the expression of alpha-smooth muscle actin (alpha-SMA), which is the hallmark of myofibroblast differentiation. These responses were attenuated by treatment with STS. In addition, STS suppressed the TGF-beta 1-induced expression of phosphorylated (p) Smad/pSmad3 expression and nuclear translocation. Furthermore, STS supressed extracellular signal-regulated kinase (ERK) phosphorylation. In conclusion, the current study demonstrates that STS exerts antifibrotic effects by modulating atrial fibroblast differentiation through ERK phosphorylation and the Smad pathway.