Objective To systematically evaluate and analyze clinical efficacy of entecavir-sequential pegylated interferon-α (ETV-sequential Peg-IFN-α) and ETV alone for treatment of patients with chronic hepatitis B (CHB). Methods Randomized controlled trial on ETV and ETV-sequential Peg-IFN-α for treatment of CHB were searched from PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure Construction (CNKI) and Wanfang database by computer, clinical studies that met the inclusion criterion were systematically evaluated and analyzed by Stata 16.0 software. Results A total of 10 literatures were included, involving 1 250 patients, 553 of whom were treated with ETV-sequential Peg-IFN-α, 697 patients were treated with ETV alone, there was no significant difference in baseline characteristics between two groups of patients (all P>0.05). HBsAg conversion rate, HBsAg clearance rate, HBeAg conversion rate and HBeAg clearance rate in ETV-sequential Peg-IFN-α trial group were all higher than those in ETV control group, differences were statistically significant (all P < 0.05). Conclusion In the antiviral treatment of CHB, therapeutic effect of ETV-sequential Peg-IFN-α is better than that of ETV alone.