Background <p>Helicobacter pylori (<i>H. pylori</i>) infection is a major pathogen associated with gastric cancer. However, the causal relationship between <i>H. pylori</i> infection and extra-gastric tumors has not been fully elucidated.</p> Methods <p>A two-sample Mendelian randomization (MR) study was conducted using genome-wide association study (GWAS) data on serum <i>H. pylori</i> IgG levels as the exposure variable and GWAS data on 268 benign and malignant tumors as the outcome variable. Single nucleotide polymorphisms (SNPs) associated with the exposure were identified from the OpenGWAS and GWAS Catalog databases, while those linked to the outcome were sourced from the FinnGen database. Independent MR analyses were performed on the discovery and validation cohorts. Sensitivity analyses, including heterogeneity and pleiotropy assessments, were conducted to ensure the robustness of the results. Meta-analysis was used to integrate significant findings from both cohorts.</p> Results <p>Our findings demonstrated negative causal effects of <i>H. pylori</i> infection on benign neoplasms of cranial nerves and extrahepatic bile ducts in both discovery and validation cohorts. Moreover, we found a potentially positive causal link between <i>H. pylori</i> infection and certain malignancies of the hypopharynx, kidney, lip, brain, pancreas, and neuroendocrine system, as well as malignant immunoproliferative diseases and leukemia, although these results were only observed in a single cohort. Sensitivity analyses showed no significant heterogeneity or horizontal pleiotropy in the significant MR directions, supporting the reliability of the results. Meta-analysis further confirmed the protective effect of <i>H. pylori</i> infection on benign cranial nerve and extrahepatic bile duct tumors.</p> Conclusion <p>This study revealed that <i>H. pylori</i> infection is causally associated with extra-gastric tumors, suggesting a potential protective role of <i>H. pylori</i> infection in certain benign tumors.</p>