BACKGROUND: The results of earlier observational research on the relationships between the usage of non-steroidal anti-inflammatory medicines (NSAIDs) and the risk of benign prostatic hyperplasia (BPH) have been inconsistent. METHODS: To assess these associations, we performed both univariable and multivariable Mendelian randomization (MR) studies. Instrumental variables (IVs) associated with exposures at the significance level (p < 5 × 10) were selected from a comprehensive meta-analysis conducted by the United Kingdom Biobank (UKB). Summary data for BPH were obtained from the FinnGen consortium, which comprised 30,066 cases and 119,297 controls. Sensitivity analyses were performed to evaluate heterogeneity and pleiotropy. RESULTS: We found evidence by univariable MR (UVMR) that genetically predicted NSAIDs use increased the risk of BPH (odds ratio [OR] per unit increase in log odds NSAIDs use: 1.164, 95% confidence interval [CI]: 1.041-1.302, p = 0.008). After controlling for inflammation in multivariable MR (MVMR), the link persisted (OR: 1.165, 95% CI: 1.049-1.293, p = 0.004). There were no indications of potential heterogeneity and pleiotropy in UVMR and MVMR analyses. CONCLUSION: The results of the MR estimates suggest that genetically predicted NSAIDs use may elevate the risk of BPH. This outcome prompts the imperative for deeper exploration into potential underlying mechanisms.