Sirtuin 2 (Sirt2), a NAD+-dependent protein deacetylase, is overexpressed in many hepatocellular carcinomas (HCCs) and can deacetylate many proteins, including tubulins and AKT prior to AKT activation. Here, we found that endogenous Sirt2 was upregulated in hepatitis B virus (HBV) WT-replicating cells, leading to tubulin deacetylation; however, this was not the case in HBV replication-deficient mutant-transfected cells and 1.3mer HBV WT-transfected plus reverse transcriptase inhibitor (entecavir or lamivudine) treated cells but all HBV proteins are expressed. In HBV WT-replicating cells, upregulation of Sirt2 induced AKT activation, which consequently downregulated glycogen synthase kinase (GSK-3β) and increased β-catenin levels; however, downregulation of Sirt2 in HBV non-replicating cells impaired AKT/GSK-3β/β-catenin signaling. Overexpression of Sirt2 isoform 1 stimulated HBV transcription and consequently HBV DNA synthesis, which in turn activates AKT and consequently increases β-catenin levels, possibly through physical interactions with Sirt2 and AKT. Knockdown of Sirt2 by shRNAs or inhibition by AGK2 or dominant-negative mutant expression inhibited HBV replication, reduced AKT activation, and decreased β-catenin levels. The deacetylase inactive isoform 5 of Sirt2 (Sirt2.5) also showed inhibited HBV replication from transcription and failed to activate AKT/GSK-3β/β-catenin signaling. Both the Sirt2.1 and Sirt2.5 are recruited to cccDNA but Sirt2.5 showed more recruitment. Through HBV infection, we demonstrated that Sirt2 knockdown inhibited HBV replication from transcription. Although HBx itself activates AKT and upregulates β-catenin, Sirt2-mediated signaling and upregulated HBV replication were HBx-independent. Since constitutively active AKT inhibits HBV replication, the results suggest that upregulated Sirt2 and activated AKT may balance HBV replication to prolong viral replication, eventually leading to development of HCC. Also, the results indicate that Sirt2 inhibition may be a new therapeutic option for controlling HBV infection and preventing HCC.