Enhancer of zeste homolog 2 (EZH2)gene has a prognostic role in hepatocellular carcinoma (HCC). This study aimed to identify the role of microRNAs (miRNAs) <i>let-7c-5p </i>by targeting <i>EZH2</i> in HCC. We downloaded gene and miRNA RNA-seq data from The Cancer Genome Atlas (TCGA) database. Differences in <i>EZH2 </i>expression between different groups were analyzed and the association of <i>EZH2 </i>expression with HCC prognosis was detected using Cox regression analysis. The miRNA-EZH2-pathway network was constructed. Dual-luciferase reporter assay was performed to detect the <i>hsa-let-7c-5p-EZH2. </i>Cell proliferation, migration, invasion, and apoptosis were detected by CCK-8, Wound healing, Transwell, and Flow cytometry, respectively. RT-qPCR and Western blot were used to detect the expression of <i>let-7c-5p</i> and <i>EZH2. EZH2 </i>was upregulated in HCC tumors (<i>P</i> < 0.0001). Cox regression analysis showed that TCGA HCC patients with high EZH2 expression levels showed a short survival time [hazard ratio (HR) = 1.677, 95% confidence interval (CI) 1.316-2.137; <i>P</i> < 0.0001]. Seven miRNAs were negatively correlated with <i>EZH2 </i>expression and were significantly downregulated in HCC tumor samples (<i>P</i> < 0.0001), in which <i>hsa-let-7c-5p </i>was associated with prognosis in HCC (HR = 0.849 95% CI 0.739-0.975; <i>P</i> = 0.021). We identified 14 immune cells that showed significant differences in EZH2 high- and low-expression groups. Additionally, <i>let-7c-5p </i>inhibited HCC cell proliferation, migration, and invasion and reversed the promoted effects of <i>EZH2</i> on HCC cell malignant characteristics. <i>hsa-let-7c-5p-EZH2 </i>significantly suppressed HCC malignant characteristics, which can be used for HCC prognosis.