Dietary rice bran (RB) has shown capacity to influence metabolism by modulation of gut microbiota in individuals at risk for colorectal cancer (CRC), which warranted attention for delineating mechanisms for bidirectional influences and cross‐feeding between the host and RB‐modified gut microbiota to reduce CRC. Accordingly, in the present study, fermented rice bran (FRB, fermented with a RB responsive microbe Bifidobacterium longum), and non‐fermented RB were fed as 10% w/w (diet) to gut microbiota‐intact^spf or germ‐free mice^gf to investigate comparative efficacy against inflammation‐associated azoxymethane/dextran sodium sulfate (AOM/DSS)‐induced CRC. Results indicated both microbiota‐dependent and independent mechanisms for RB meditated protective efficacy against CRC that was associated with reduced neoplastic lesion size and local‐mucosal/systemic inflammation, and restoration of colonic epithelial integrity. Enrichment of beneficial commensals (such as, Clostridiales, Blautia, Roseburia), phenolic metabolites (benzoate and catechol metabolism), and dietary components (ferulic acid‐4 sulfate, trigonelline, and salicylate) were correlated with anti‐CRC efficacy. Germ‐free studies revealed gender‐specific physiological variables could differentially impact CRC growth and progression. In the germ‐free females, the RB dietary treatment showed a ∼72% reduction in the incidence of colonic epithelial erosion when compared to the ∼40% reduction in FRB‐fed mice^gf. Ex vivo fermentation of RB did not parallel the localized‐protective benefits of gut microbial metabolism by RB in damaged colonic tissues. Findings from this study suggest potential needs for safety considerations of fermented fiber rich foods as dietary strategies against severe inflammation‐associated colon tumorigenesis (particularly with severe damage to the colonic epithelium).