BACKGROUND AND OBJECTIVE: Hepatocellular carcinoma (HCC) ranks among the most prevalent cancers globally, representing a significant challenge to healthcare systems around the globe. Hepatitis B virus (HBV) infection is the primary causal factor for HCC, alongside various other risk elements. Timely intervention for HBV holds the potential to effectively prevent the onset of HCC. However, standard first-line treatments, such as nucleos(t)ide analogues and interferon-α (IFN-α), seldom result in complete HBV eradication. Additionally, emerging approaches such as gene editing are still immature and entail certain risks. This review aimed to characterize the roles of the APOBEC3 (A3) family in HBV-associated disease, particularly HCC, with the goal of presenting a novel perspective for its management. METHODS: A literature search of the relevant databases was conducted, with a focus on recent and key publications in the English language. The search strategy included terms related to APOBEC3, HBV, and HCC. KEY CONTENT AND FINDINGS: The APOBEC3 (A3) protein family, whose members function as DNA cytidine deaminases, exhibits the capacity to impede viruses and modulate a variety of tumor types. Members of the A3 family exert a dual effect in HBV-induced HCC (HBV-HCC), both demonstrating antiviral efficacy and potentially contributing to carcinogenic mutations that promote cancer initiation and advancement. CONCLUSIONS: The paradoxical nature of the A3 protein family-possessing both antiviral properties and carcinogenic potential-highlights its complex role in HBV-HCC. Understanding these regulatory mechanisms may provide novel insights into developing innovative management strategies for HBV-HCC.