Objective To investigate the potential causal relationship between specific oral microbiota and peptic ulcer disease (PUD) using a Mendelian randomization (MR) approach. Methods The genome-wide association study (GWAS) data from East Asian populations was utilized to perform a two-sample MR analysis to determine the causal relationship between oral microbiota and PUD. The MR analysis was primarily conducted using the inverse-variance weighted (IVW) method, supplemented by MR-Egger and weighted median methods. Heterogeneity and pleiotropy were assessed, and the leave-one-out method was employed to evaluate the stability of the MR results. Results There was a complex association between specific bacterial genera of the oral microbiota and PUD. Prevotella was found to potentially promote duodenal ulcers while exerting a protective effect against gastric ulcers. Campylobacter and Streptococcus demonstrated differing effects on gastric and duodenal ulcers. Furthermore, Fusobacterium and Haemophilus_A were positively associated with peptic ulcers, suggesting an increased risk of gastroduodenal ulcer development. Conclusion This study explores the causal relationship between oral microbiota and PUD, providing new insights into the prevention and treatment of PUD mediated by oral microbiota.