Hepatitis B virus (HBV) infection remains a significant global health challenge, characterized by chronic liver inflammation and compromised antiviral immunity. The outcome of HBV infection and associated liver pathogenesis is influenced mainly by the host innate immune and inflammatory responses. Characterizing the mechanisms underlying these responses might provide new therapeutic strategies for HBV treatment. HECT domain and RCC1-like domain 2 (HERC2) belongs to the large HERC family of ubiquitin E3 ligases, which are implicated in tissue development and inflammation. We initially observed that hepatic tissues from chronic hepatitis B patients express lower levels of HERC2 compared with healthy donors. In this study, we identified HERC2 as a critical suppressor of HBV infection. Hepatocyte-specific HERC2-deficient mice exhibited increased susceptibility to HBV infection. Our findings demonstrate that HERC2 directly interacts with TBK1, a vital regulator of the innate immune response, mediating its K33 ubiquitination and activation. This HERC2-mediated activation of TBK1 triggers a signaling cascade that culminates in the activation of transcription factors IRF3 and IRF7, subsequently driving the production of type I interferons, crucial antiviral cytokines. The findings deepen our understanding of the molecular mechanisms underlying HBV pathogenesis and present potential avenues for developing targeted immunomodulatory therapies to combat HBV infection more effectively.