Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. Hepatocarcinogenesis is a multistep process mainly associated with persistent infection with hepatitis B (HBV) or C (HCV) viruses and always involving the accumulation of genetic alterations over decades of chronic liver disease. Mutations in TP53 and CTNNB1 genes are considered the cancer drivers for HCC development with variable frequencies depending on the etiology. Here we present a comprehensive review evaluating somatic mutations in TP53 and CTNNB1 genes in HBV- and HCV-related HCCs. Moreover, we report the mutational analysis of TP53 (exons 4–9) and CTNNB1 (exon 3) as well as PIK3CA (exon 9) genes in HCC from Southern Italy. The overall mutation frequency of TP53 and CTNNB1 was 33.3%, while hotspot variations in PIK3CA were completely absent. CTNNB1 mutations were significantly associated with young age (P = 0.019) and moderately/poorly differentiated HCV-related HCC (P = 0.015). The extended analysis of genetic alterations will help to identify molecular markers for liver cancer prevention, diagnosis and treatment of HBV and HCV-associated liver cancer.