<p>Observational studies have found that HMGCR inhibitors can be used to treat chronic viral hepatitis. In this study, to explore the potential mechanism of HMGCR inhibitors in treating Chronic hepatitis B (CHB), two-sample and two-step Mendelian randomization (MR) were used to investigate the causal relationship between HMGCR inhibitors and the mediating role of circulating metabolites. GWAS data of expression quantitative trait loci eQTLs of HMGCR inhibitors, 168 circulating metabolites, CHB, and myocardial infarction were obtained from the IEUOpenGWAS project. Random effects inverse-variance weighted (IVW) was the main causal analysis method, and the MR–Egger regression method was used as a supplementary analysis method. Cochran’s Q test and I² statistic were used to determine the heterogeneity of SNPs. The intercept terms of the MR–Egger method and MR-PRESSO were used for pleiotropy analysis, and leave-one-out was used for sensitivity analysis. Mediation effect analysis was used to evaluate the mediating role of the circulating metabolites. Genetic variations in the drug target genes of HMGCR inhibitors were associated with a reduced risk of chronic hepatitis B and myocardial infarction (<i>P</i> &lt; 0.05). Eight circulating metabolites had a significant causal relationship with HMGCR inhibitors and CHB. After further calculation of the mediation effect, citrate was used as a mediating variable between HMGCR inhibitors and CHB, with a mediation effect of − 0.015 and a mediation ratio of 9.769%. HMGCR inhibitors can significantly reduce the risk of CHB, and the circulating metabolite citrate may mediate this association. However, this study has certain limitations. The short-term effects of HMGCR inhibitors on CHB could not be assessed, and partial overlap between the GWAS data for HMGCR inhibitors and circulating metabolites may introduce bias in estimating causal effects.</p>