This study is to investigate the anti-Schistosomiasis liver fibrosis effects of chlorogenic acid (CGA) on IL-13/miR-21/Smad7 signaling interactions in hepatic stellate LX2 cell line and Schistosome-infected mice. The transfection was based on the GV273-miR-21-EGFP and GV369-miR-21-EGFP lentiviral system to up- or down-regulate miR-21 gene in LX2 cells. The mRNA expression of miR-21, Smad7 and connective tissue growth factor (CTGF) and protein expression of Smad7, CTGF, Smad1, p-Smad1, Smad2, p-Smad2, Smad2/3, p-Smad2/3, TGF-β receptor Ⅰ and α-SMA were assayed. Pathological manifestation of hepatic tissue was assessed for the degree of liver fibrosis in animals. As a result, CGA could inhibit the mRNA expression of miR-21, and promote Smad7 and inhibit CTGF mRNA expression. Meanwhile, CGA could significantly lower the protein level of CTGF, p-Smad1, p-Smad2, p-Smad2/3, TGF-β receptor I, α-SMA，and elevate Smad7 protein level. In vivo, with treatment of CGA, the signaling molecules of IL-13/miR-21/Smad7 interactions were markedly regulated. CGA could also reduce the degree of liver fibrosis in pathological manifestation. In conclusion, CGA could inhibit Schistosomiasis-induced hepatic fibrosis through IL-13/miR-21/Smad7 signaling interactions in LX2 cells and Schistosome-infected mice, which might serve as an anti-fibrosis agent for treating schistosomiasis liver fibrosis.