Background The association between Helicobacter pylori (HP) infection and coronary heart disease (CHD) is controversial. This study aimed to investigate the effect of H. pylori eradication on CHD, especially in terms of age and sex. Materials and Methods From May 2003 to March 2022, 4765 subjects with H. pylori infection and without CHD (median follow‐up: 51 months) were prospectively enrolled. The participants were categorized into two groups: H. pylori eradication and H. pylori non‐eradication. After propensity‐score matching (PSM), the effect of H. pylori eradication on CHD was analyzed using Cox proportional hazards. Results There were no significant differences in age, sex, alcohol consumption, smoking habits, history of diabetes, hypertension, and dyslipidemia, and aspirin intake between the eradication and non‐eradication groups (3783 vs. 982) before and after PSM. Multivariate analysis after PSM showed that H. pylori eradication (HR: 0.489, CI: 0.314–0.761, p = .002), age (HR: 1.027, CI: 1.007–1.047, p = .007), hypertension (HR: 2.133, CI: 1.337–3.404, p = 001), dyslipidemia (HR: 1.758, CI: 1.086–2.848, p = .022), and aspirin intake (HR: 2.508, CI: 1.566–4.017, p < .001) were associated with CHD development. H. pylori eradication prevented CHD in males ≤65 years (HR: 0.133, CI: 0.039–0.455, p = .001), but not in those aged >65 years (p = .078) (p for interaction = .022). In contrast, females aged >65 years (HR: 0.260, CI: 0.110–0.615, p = .002) were protected by H. pylori eradication and not those ≤65 years (p = .485) (p for interaction = .003). This preventive effect increased more after PSM, particularly in males ≤65 years and females >65 years. Conclusions H. pylori eradication prevented CHD and this effect was different depending on age and sex.