Hepatocellular carcinoma (HCC) is a highly malignant and heterogeneous tumor with poor prognosis. Cancer driver genes (CDGs) play an important role in the carcinogenesis and progression of HCC. In this study, we comprehensively investigated the expression, mutation, and prognostic significance of 568 CDGs in HCC. A prognostic risk model was constructed based on seven CDGs (CDKN2C, HRAS, IRAK1, LOX, MYCN, NRAS, and PABPC1) and verified to be an independent prognostic factor in both TCGA and ICGC cohorts. The low-score group, which showed better prognosis, had a high proportion of CD8(+) T cells and elevated expression of interferon-related signaling pathways. Additionally, we constructed a nomogram to extend the clinical applicability of the prognostic model, which exhibits excellent predictive accuracy for survival. Our study showed the important role of CDGs in HCC and provides a novel prognostic indicator for HCC.