Liver fibrosis is the most common pathological outcome and the most severe complication of chronic liver diseases. Accumulating evidence suggests that miRNAs are involved in cell proliferation, differentiation, apoptosis, as well as the occurrence and development of various diseases. In this study, we found that the expression of let-7a was markedly decreased in the liver tissue samples and blood samples from patients with liver fibrosis compared with healthy volunteers. Furthermore, let-7a was downregulated in the liver tissues and blood samples in mouse models of liver fibrosis. Further analysis indicated that let-7a suppresses the activation level of hepatic stellate cells (HSCs). In addition, overexpression of let-7a reduced cell viability and promoted apoptosis of HSCs. Western blot analysis showed that let-7a might inhibit HSCs through TGFβ/SMAD signaling pathway. The present study provides a potential accurate target and vital evidence to better understand the underlying pathogenesis for early diagnosis and treatment of liver fibrosis.