Despite the development in hepatocellular carcinoma (HCC) treatment in recent years, the therapeutic outcome of HCC remains unfavourable. This study examines the prognosis of HCC from a genetic level using clinical databases and single‐cell data to identify genes with a high prognostic value. Three up‐regulated genes (UBE2S, PTTG1, and CDC20) and two down‐regulated genes (SOCS2 and DNASE1L3) in HCC tissues were identified. Various analyses confirmed its correlation with tumour stage (p < 0.01) and patient survival time (log‐rank p < 0.001). Immune analysis, single‐cell analysis, and gene set enrichment analysis (GSEA) were employed to provide insight on how they affect cancer progression, and we observed a close relation between these genes and tumour immune infiltration. Eventually, we constructed a risk score system that risk score = (0.0465) × UBE2S + (0.1851) × CDC20 + (−0.0461) × DNASE1L3 + (−0.2279) × SOCS2 (5‐year area under curve = 0.706). The risk score system may serve as an effective novel prognostic system for HCC patients. This study might provide novel ideas for prognostic or therapeutic biomarkers for HCC.