BACKGROUND: Previous studies have found that antidepressants could reduce the risk of IBD, but the results are controversial. Therefore, a drug-target Mendelian randomization was applied to explore the casual relationship between antidepressants and IBD, aiming to identify new preventive uses for the drugs. METHODS: Target genes corresponding to classic SSRI drugs were obtained from the DrugBank database. eQTL Data was collected from the eQTLGen Consortium database. GWAS data for IBD were retrieved from the FinnGen dataset. The IVW-MR and SMR methods were used for the analysis. Heterogeneity was assessed using the Cochran's Q test, and sensitivity analyses was conducted to verify the reliability of the results. RESULTS: The IVW-MR analysis indicated a significant correlation between SIGMAR1 and risk of IBD, CD and UC. The OR with 95%CI for IBD was 0.925 (0.885-0.968), for CD was 0.91(0.845-0.979), for UC was 0.942(0.895-0.991). The SMR analysis indicated a significant correlation between SLC29A4 and risk of IBD, CD and UC. The OR with 95%CI was 1.524(1.265-1.784) for IBD, 1.767(1.343-2.19) for CD and 1.613(1.316-1.909) for UC. There were no significant genetic associations between serotonin concentration and IBD. The sensitivity analysis suggested no evidence of heterogeneity or pleiotropy among the reported results. CONCLUSION: Activation of SIGMAR1 could reduce the risk of IBD, while activation of SLC29A4 could increase the risk of IBD. Further research is warranted to fully understand the potential role of SSRIs targeted genes in the development and progression of IBD.