The inhibitory effects of the tumor necrosis factor-alpha (TNF-alpha) antibody infliximab (IFX) on colitis are well established. Since IFX dosing is weight-based and associated with various side effects, there is a growing interest in identifying combination therapies that can enhance its efficacy, particularly in overweight inflammatory bowel disease (IBD) patients, to maximize the anti-inflammatory effect while minimizing the required dose. Our research revealed that overweight IBD patients present decreased vitamin D levels in the intestinal epithelium alongside elevated TNF-alpha levels. In mice fed a high-fat diet (HFD) for four weeks, treatment with the vitamin D analog palicalcitol (PAL) reduced lipid synthesis and TNF-alpha production in intestinal epithelial cells (IECs). In a 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced experimental colitis model, PAL treatment mitigated TNF-alpha-induced damage to the intestinal epithelial barrier and reduced the activation of Th1 and Th17 cells in the lamina propria, thereby reducing colitis development in HFD-fed mice. Notably, the combination of IFX and PAL was more effective than IFX alone in treating colitis in these mice. Overall, our findings suggest that vitamin D inhibits TNF-alpha production by reducing lipid synthesis in IECs, thereby enhancing IFX therapy in overweight IBD patients.