OBJECTIVE: To analyze the clinical effectiveness of Entecavir (ETV) and Tenofovir Disoproxil Fumarate (TDF) Tablets for the treatment of chronic hepatitis B (CHB). METHODS: Clinical data from 100 CHB patients admitted to our hospital from April 2022 to April 2024 were retrospectively reviewed. Of these, 45 cases in the control group received ETV, and 55 cases in the research group received TDF tablets. Data on clinical effectiveness, safety (creatine kinase elevation, fatty liver, and lactic acidosis), hepatic function (total bilirubin [TBIL], alanine aminotransferase [ALT], and aspartate aminotransferase [AST]), viral markers (hepatitis B virus-deoxyribonucleic acid [HBV-DNA] and hepatitis B surface antigen [HBsAg]), and quality of life (the MOS 36-Item Short-Form Health Survey [SF-36], assessing cognitive, physical, emotional, role, social functions) were comparatively analyzed. RESULTS: The research group showed an evidently higher overall effective rate and a markedly lower incidence of total adverse reactions than the control group (all P<0.05). Additionally, statistically lower post-treatment TBIL, ALT, AST, HBV-DNA, and HBsAg levels and higher SF-36 scores across all five dimensions were observed in the research group (all P<0.05). Moreover, the research group showed markedly higher negative conversion rates of HBsAg after treatment compared to the control group (P<0.05). CONCLUSION: TDF provides better clinical effects in the treatment of CHB than ETV and thus it is worthy of clinical promotion.