Cranberries contain phytochemicals with potent antioxidant properties. Phenethyl isothiocyanate (PEITC) is abundant in crucifers and possesses anti-cancer and anti-inflammatory properties. These food additives can alter gut microbiota and improve the host's health. Microbiome and microbial metabolome interactions with the host's cells help maintain gastrointestinal (GI) tract homeostasis. Cranberry and PEITC enriched diets were fed to wild-type (WT) and Nrf2 knockout (KO) mice, including those challenged with dextran sulfate sodium (DSS), and their gut microbiomes and metabolomes were examined. Relative abundances of Deferribacteres, Epsilonbacteraeota, and Proteobacteria decreased, while Firmicutes and Verrucomicrobia increased in the DSS-challenged mice samples. These trends were reversed by PEITC and cranberry enriched diets. The diets also preserved the Firmicutes-to-Bacteroidetes ratio, an endpoint associated with gut inflammation and obesity. DSS challenge altered production of several metabolites. Nrf2 KO mice samples had lower concentrations of short-chain fatty acids (SCFA) and amino acids, and higher concentrations of secondary bile acids. Nrf2 KO mice microbiomes exhibited higher richness and diversity. PEITC and cranberry enriched diets positively affected hosts' microbiomes and boosted several microbial metabolites. Phenotypic expression of Nrf2 impacted the microbiota and metabolic reprogramming induced by DSS-mediated inflammation and dietary supplements of cranberry and PEITC.