Abstract Background Millions of individuals globally suffer from Inflammatory bowel diseases (IBDs). There is a dearth of large population-based investigations on lipid metabolism and IBDs, and it is unclear whether lipid-lowering drugs target IBDs causally. Consequently, the aim of this study was to investigate the effects of lipid-lowering medication targets on the occurrence and progression of IBDs. Methods Among the more than 400,000 participants in the UK Biobank cohort and the more than 170,000 participants in the Global Lipids Genetics Consortium, a total of nine genes linked to lipid-lowering drug targets were obtained (ABCG5/ABCG8, APOB, APOC3, LDLR, LPL, HMGCR, NPC1L1, PCSK9, and PPARA). IBD data were acquired from de Lange et al. (patients/sample size of IBDs: 25042/59957; ulcerative colitis (UC): 12366/45,975; Crohn's disease (CD): 12194/40,266) and the FinnGen cohort (patients/total sample size of IBDs: 4420/176,899; CD: 1520/171,906; UC: 3325/173,711). All four datasets were cross-combined for validation via Mendelian randomization analysis, and potential mediating factors were explored via mediation analysis. Results Genetically proxied APOC3 inhibition was related to increased IBD risk (odds ratio (95% confidence interval): 0.87 (0.80–0.95); P