ABSTRACT The existing studies indicate that the lipidome may be associated with inflammatory bowel disease (IBD). However, most of the results of previous studies are based on epidemiological or observational studies. Meanwhile, the causal association between different lipids and inflammatory bowel diseases, as well as whether inflammatory proteins act as mediators, remains unclear. We employed Mendelian randomized (MR) analysis to investigate the causal relationship between lipidome and IBD (ulcerative colitis and Crohn's disease). We mainly used the IVW method for MR analysis and further evaluated heterogeneity and pleiotropy. Additionally, we explored whether circulating inflammatory proteins play a mediating role in the pathway from the lipidome to IBD. In our MR study, we identified causal relationships between four classes of lipids (sterol ester, phosphatidylcholine, sphingomyelin, and phosphatidylethanolamine) and IBD. The risk of IBD is positively associated with the levels of 6 inflammatory proteins (CCL19, CCL4, CD5, CD6, IL‐10α, and TNFSF12). In the mediation analysis, we identified two circulating inflammatory proteins (CD6, CCL4) that play a mediating role between the lipidome and IBD. Plasma lipidome was causally associated with IBD, and circulating inflammatory proteins serve as mediating factors in the pathway from lipidome to IBD.