Accumulating evidence indicates that hepatic stellate cells (HSCs) are the central mediators and major effectors in the development of hepatic fibrosis. It is well-known that regulation of cell proliferation and apoptosis are potential strategies to block the activation of HSCs. Recently， several studies have revealed that induction of HSC senescence could prevent and cure the liver fibrosis. In our previous work， we have demonstrated that the natural product tetramethylpyrazine (TMP) could inhibit the activation of HSCs and ameliorate hepatic fibrosis. The aim of this study was to identify a new role of TMP in the regulation of activated HSC senescence and to elucidate the underlying mechanisms. In this study， our data showed that TMP could promote HSC senescence in vivo and in vitro. Moreover， TMP affected the cell cycle and telomerase activity. We further demonstrated that P53 siRNA or P53 pharmacological inhibitor PFT-α abrogated the TMP-induced HSC senescence in vitro. Meanwhile， similar results were obtained in vivo. Further studies indicated that TMP promoted the expression of P53 through a YAP inhibition-dependent mechanism. Moreover， silencing YAP enhanced TMP induction of activated HSC senescence. Collectively， our results suggested that TMP inhibited the activation of HSCs by inducing senescence and had therapeutic implication for the treatment of liver fibrosis.