Ectopic expression of HOX-containing genes is closely related to carcinogenesis, acting as either tumor suppressors or oncogenes. A preliminary bioinformatics analysis showed that HoxB7 is a possible target of let-7c. In this study, we aimed to investigate the relationship between HoxB7 and let-7c in liver carcinogenesis. We found that HoxB7 was upregulated in hepatocellular carcinoma (HCC) tissues and cells and negatively correlated with survival time, whereas let-7c was downregulated and positively correlated with survival time in patients with HCC. Let-7c overexpression suppressed proliferation, migration but promoted cell apoptosis in HCC cells. We validated that HoxB7 is a target of let-7c. Consistently, let-7c overexpression reversed the promotional effects of HoxB7 on proliferation and migration in HCC cells, and increased the cell apoptotic rate reduced by HoxB7. Furthermore, let-7c overexpression reversed the promotional effect of HoxB7 on tumor growth in subcutaneous HCC tumor model. Our data suggest that the let-7c/HoxB7 axis regulates HCC development, which may provide a novel therapeutic strategy for the treatment of HCC.