The causal relationship between inflammatory bowel disease (IBD) and diabetes mellitus remains unclear. The aim of this study was to delve into this association and investigate the correlation between AMP-activated protein kinase (AMPK), a target gene of metformin, and the risk of developing IBD. Researchers conducted a bidirectional two-sample Mendelian randomization analysis to examine causal relationships between IBD, including ulcerative colitis and Crohn disease (CD), and diabetes mellitus, encompassing both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). Additionally, this study utilized AMPK-related variants associated with HbA1c (%) as instrumental variables for the metformin target gene AMPK to further investigate their association with the risk of IBD. The inverse variance weighted method was used as the primary analytical approach. Mendelian randomization analysis revealed a suggestive association between IBD and T1DM (P = .024). CD was associated with an increased risk of T1DM (P = .011). In the reverse analysis, T1DM also increased the risk of IBD (P = .043). No causal relationship was found between IBD and T2DM in either the forward or reverse analyses. In addition, this study did not find any significant effect of AMPK on IBD. In conclusion, this study suggests a bidirectional association between IBD and T1DM, in which CD may increase the risk of T1DM. However, no causal relationship was found between IBD and T2DM. Furthermore, our findings revealed that the metformin's target gene AMPK had no significant effect on the onset of IBD.