Background: Entecavir (ETV) has been widely used in the clinical treatment of the Hepatitis B Virus (HBV). However, whether ETV is helpful in the recovery of T cell immune function remains unclear. Objectives: We aimed to assess the effects of ETV on serum HBV-DNA, interferon-γ (IFN-γ), and pregenomic RNA (pgRNA) in patients with infection. Methods: The clinical data of 300 HBV patients admitted from January 2017 to January 2019 were retrospectively analyzed, of whom 193 cases administered with ETV were assigned to an observation group, and the remaining 107 untreated cases (who refused treatment) were assigned to a blank control group. Their liver function [aspartate aminotransferase (AST) and alanine aminotransferase (ALT)], serum HBV markers [hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg)], IFN-γ, HBV-DNA, HBV pgRNA, negative conversion rates of HBeAg and HBV-DNA, and adverse reactions were compared. Results: The levels of HBsAg, IFN-γ, HBV-DNA, and HBV pgRNA were lower in the observation group than in the blank control group 12, 24, and 48 weeks after treatment (P < 0.05). The HBeAg and HBV-DNA negative conversion rates of the observation group were higher than those of the blank control group 12, 24, and 48 weeks after treatment (P < 0.05). Conclusions: Antiviral therapy with ETV can inhibit the replication of HBV-DNA, increase the HBV-DNA negative conversion rate, enhance immune function, and reduce the expression of HBV pgRNA in HBV patients.