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Enhancing NAD+ levels with nicotinamide riboside (NR) confers anti-inflammatory effects in human disease, although immunoregulatory mechanisms remain poorly characterized. We previously showed that ex vivo NR supplementation of primary CD4+ T cells from psoriatic individuals dampened immune responsiveness. To validate this in vivo, we performed a randomized, placebo-controlled NR supplementation study in individuals with mild-to-moderate psoriasis. Participants received oral NR (500 mg twice daily) or matching placebo for 4 weeks, with blood samples collected at baseline and after supplementation. NR reduced Th17 immune responsiveness. Bulk CD4+ T cell RNA-seq identified induction of the SLIT-ROBO signaling pathway. NR supplementation increased circulating SLIT2 levels and enhanced SLIT2 production in dermal fibroblasts. Pharmacologic and genetic interrogation in CD4+ T cells and fibroblasts demonstrated that SLIT2, acting through the ROBO1 receptor, inhibited Rho GTPase signaling, thereby attenuating canonical Th17 polarization and fibroblast inflammatory activation. These findings indicate that NAD+ augmentation exerts anti-inflammatory effects in psoriasis through SLIT2-ROBO1-mediated crosstalk between dermal fibroblasts and circulating CD4+ T cells, leading to suppression of Th17-driven inflammation.