Background While numerous studies have indicated that infection with Helicobacter pylori (H. pylori) may elevate the risk of coronary atherosclerosis, the potential causal relationship remains uncertain. Therefore, we used Mendelian randomization (MR) analysis to investigate the causal association between H. pylori infection and coronary atherosclerosis. And quantify the potential mediating pathways.Methods We employed a two-step Mendelian randomization model to evaluate the intermediate effects of risk elements such as inflammatory markers, lipid characteristics, and glucose levels on the causal connections between H. pylori infection and the development of coronary atherosclerosis. A multivariable Mendelian randomization (MVMR) study was designed to estimate potential mediators and their corresponding mediation proportions.Results H. pylori infection has a positive causal relationship with coronary atherosclerosis (n = 11 SNPs, OR = 1.162, 95% CI: 1.006–1.342, p = 0.041). Two causal mediators, C-X-C motif chemokine 10 and HDL-C, were identified after a thorough screening of all potential causal mediators, which accounted for 17.8% and 9.07% of the mediating effect, respectively. Importantly, these results remained robust in sensitivity analyses.Conclusion Our study substantiates a causal relationship between H. pylori infection and coronary atherosclerosis, which is, to some extent, mediated by the influence of CXCL10 and HDL-C. Intervening on CXCL10 and HDL-C may reduce the susceptibility to coronary atherosclerosis.