Oral nucleotide analogues (NAs) and peginterferon-α injections are commonly used for the treatment of patients with chronic hepatitis B (CHB). This study aims to evaluate the effects of different antiviral therapies on the degree of liver inflammation and fibrosis in CHB patients. This was a retrospective cohort study. A total of 101 CHB patients were admitted to the Liver Center of Xiamen Hospital of Traditional Chinese Medicine from 2017 to 2021 and were divided into three groups for different antiviral treatments: NAs therapy group (n = 36), peginterferon-α therapy group (n = 38) and nonantiviral therapy group (n = 27). The differences in degrees of liver inflammation and liver fibrosis between two histopathologic biopsies before and after treatment were analysed and compared to evaluate the efficacy of different treatments. The degrees of liver inflammation and liver fibrosis were improved after NAs or peginterferon-α therapy. In terms of improving the degree of liver inflammation, peginterferon-α therapy (74%) and NAs therapy (44%) were better than nonantiviral therapy (11%, p <
0.05), although no significant difference was shown between peginterferon-α therapy and NAs therapy (p = 0.974). For liver fibrosis improvement, peginterferon-α therapy showed significantly better efficacy than NAs therapy (68% vs. 33%, p = 0.044), while NAs therapy was better than nonantiviral therapy (33% vs. 11%, p = 0.028). Peginterferon-α and NAs can significantly improve the degree of liver inflammation and liver fibrosis in CHB patients. Peginterferon-α is superior to NAs in delaying and reversing liver fibrosis. This study provides a new basis for peginterferon-α therapy to prevent progression of fibrosis in CHB patients.