Background and Purpose: Macrophages not only can maintain gut immune homeostasis by driving clearance of infection, but also can prevent chronic inflammation and induce tissue repair. Macrophages are a heterogenous group of cells whose characteristics are determined by tissue microenvironment and metabolism. Since macrophages play an important role in inflammatory disorders such as inflammatory bowel disease (IBD), they can be a potential therapeutic target. Experimental Approach: Here we show an IBD therapeutic candidate LMT503, a substrate which modulates NADH quinone oxidoreductase 1, which enhances NAD+ and induce anti-inflammatory macrophage polarization. To determine the anti-inflammatory effect of LMT503, a dextran sulfate sodium (DSS)-induced colitis mouse model was used in this study. Key Results: Treatment of bone marrow derived macrophages (BMDMs) with LMT503 increased IL-10 and Arg1 levels but decreased levels of TNF-α, iNOS, and IL-6. LMT503 also increased levels of SIRT1, SIRT3, and SIRT6, suggesting that macrophages were driven to an anti-inflammatory character. In a murine DSS-induced colitis model, oral treatment with LMT503 ameliorated colonic inflammation and decreased infiltrating monocytes and neutrophils. Although NAD+ enhancement did not alter CX3CR1intCD206- or CX3CR1hiCD206+ colon macrophage population, it decreased levels of TNF-α and iNOS and increased IL-10 level, with colonic macrophages showing an anti-inflammatory character shift. Depletion of CX3CR1 expressing gut resident macrophages abrogated the immune regulatory effect of LMT503 in the colon. Conclusion and Implications: These data suggest that LMT503 is a therapeutic candidate that can target macrophages to drive polarization with an immunosuppressive character and ameliorate IBD.