Background and Purpose: Extracellular matrix (ECM) is mainly derived from activated hepatic stellate cells (HSC), and its excessive deposition is one of the characteristics of liver fibrosis. Monomer derivative of paeoniflorin (MDP) inhibits inflammatory responses. However, the role and fundamental mechanism of MDP in liver fibrosis was still unclear. Experimental Approach: The effect of MDP was evaluated on CCl4-induced C57BL/6J mice and TGF-β1-induced LX-2 cells. The level of SA-β-Gal was detected by SA-β-Gal kits. The cell cycle was evaluated by flow cytometry. The expression of p16, p21, α-SMA and Col. I proteins were analyzed by qRT-PCR, Western blots and immunofluorescence staining and IHC staining. The pathological changes of liver tissue were evaluated by histological analysis. Key Results: We demonstrated that MDP inhibited the progression of liver fibrosis in vivo and in vitro, concomitant with the elevated expression of Ago2, miR-708 and p53 as well as the downregulated expression of ZEB1. MDP could combined with Ago2. Upregulation of miR-708 and p53 and downregulation of ZEB1 increased the number of SA-β-Gal-positive HSCs and the expression levels of p16 and p21 as well as decreased the expression of α-SMA and Col. I in activated HSCs. Meanwhile, miR-708 directly targeted ZEB1, thus inhibiting the mRNA of ZEB1. ZEB1 could bind to the E‐box of p53 promoter and restrain its promoter activity as well as thus block the expression of p53. Conclusion and Implications: MDP could induce senescence of activated HSCs via regulating Ago2/miR-708/ZEB1/p53 aixs and may be applied to treat liver fibr