Macrophages can maintain gut immune homeostasis by driving clearance of infection, but also can prevent chronic inflammation and induce tissue repair. Reduced nicotinamide adenine dinucleotide (NAD(+)) levels in macrophages have been reported to be associated with the onset of severe colitis. Given that dysregulation of gut macrophages plays a significant role in inflammatory bowel disease (IBD), they represent a potential target for novel therapies. Here we show an IBD therapeutic candidate LMT503, a substrate that modulates NADH quinone oxidoreductase (NQO1), which induces anti-inflammatory macrophage polarization by NAD(+) enhancement. To determine the anti-inflammatory effect of LMT503, a dextran sulfate sodium (DSS)-induced colitis mouse model was used in this study. Treatment of bone marrow-derived macrophages (BMDMs) with LMT503 increased IL-10 and Arg1 levels but decreased levels of TNF-alpha, 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 CX(3)CR1(int)CD206(-) or CX(3)CR1(hi)CD206(+) colon macrophage population, it decreased levels of TNF-alpha and iNOS and increased IL-10 level, with colonic macrophages showing an anti-inflammatory character shift. Depletion of CX(3)CR1 expressing gut resident macrophages abrogated the immune regulatory effect of LMT503 in the colon. These data suggest that LMT503 is a therapeutic candidate that can target macrophages to drive polarization with an immunosuppressive character and ameliorate IBD.