Objective To investigate the association of serum exosomal microRNAs （miRNAs） with hepatic inflammatory injury and histological outcomes in patients with chronic hepatitis B （CHB）. Methods Peripheral serum samples were collected from six healthy adults and six patients with CHB，and size exclusion chromatography was used to extract exosomes. Small RNA sequencing and transcriptomic analysis were used to identify the serum exosomal miRNAs associated with liver inflammatory injury and fibrosis，and quantitative real-time PCR was used for validation in a mouse model of acute liver injury induced by lipopolysaccharide/D-galactosamine，a rat model of liver fibrosis induced by carbon tetrachloride，and 84 CHB patients undergoing liver biopsy twice before and after treatment. The independent-samples t test was used for comparison of normally distributed continuous data between two groups； an analysis of variance was used for comparison between multiple groups，and the Tukey test was used for further comparison between two groups. The Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups； the Kruskal-Wallis H test was used for comparison between multiple groups，and the Dunn test was used for further comparison between two groups. The chi-square test or the Fisher’s exact test was used for comparison of categorical data between groups. The univariate and multivariate Logistic regression analyses were used to investigate influencing factors. Results Abnormal expression of serum exosomal miR-122-5p was observed in patients with CHB，and it was downregulated in patients with confluent necrosis and advanced fibrosis. In the mouse model of acute liver injury and the rat model of liver fibrosis，compared with the control group，the model group had a significant reduction in the expression level of miR-122-5p in the liver （P=0.048 and 0.014），and compared with the patients with mild liver injury，the patients with severe confluent necrosis and advanced fibrosis showed a significant reduction in the expression level of miR-122-5p in liver tissue （P<0.05）. Among the 84 CHB patients，the patients with severe hepatic confluent necrosis or advanced liver fibrosis had a significantly lower expression level of serum exosomal miR-122-5p than those with mild liver injury （P<0.001 and P=0.003）. The multivariate Logistic regression analysis showed that the expression level of miR-122-5p was an independent influencing factor for confluent necrosis （odds ratio ［OR］=0.001，95% confidence interval ［CI］：0.000‍ ‍—‍ ‍0.037，P=0.005） and liver fibrosis degree （OR=0.568，95%CI：0.331‍ ‍—‍ ‍0.856，P=0.019）. In addition，compared with the patients with low expression of miR-122-5p，the patients with high expression of miR-122-5p before treatment had a significantly higher reversal rate of liver fibrosis after 72 weeks of antiviral therapy （64.3% vs 38.1%，P=0.029）. Conclusion Serum exosomal miR-122-5p in CHB patients is closely associated with the progression of hepatic confluent necrosis and fibrosis，and the reduction in the expression level of miR-122-5p may aggravate hepatic confluent necrosis，promote the progression of fibrosis，and affect the histological outcome of CHB patients after antiviral therapy.