ABSTRACT Background Prostate cancer is one of the most common malignancies in men worldwide, and prostate-specific antigen (PSA) screening is widely used for its early detection. Drug use may affect PSA levels, but the effect for most drugs is currently unknown. Methods This study first investigated drugs related to PSA changes through the Food and Drug Administration Adverse Event Reporting System (FAERs) database, and then used a Mendelian randomization (MR) method to explore the causal relationship between specific drugs and PSA changes using a genome-wide association study (GWAS) data. The statistical analysis software SAS and R were used in the study. Results Through analysis of the FAERs database, 22 drugs were found to be associated with an increase in PSA, and 14 drugs were associated with a decrease in PSA. MR analysis showed that the use of tamsulosin may lead to an increase in PSA. Heterogeneity test, horizontal pleiotropy test and leave-one-out Analysis verified the stability of the results. MR analyses for other drugs did not show statistical significance. Conclusion This study provided a basis for better understanding the impact of medications on prostate health, helping to avoid overdiagnosis or underdiagnosis of high-risk patients. However, research still requires larger-scale validation and in-depth exploration.