High-fat (H) and calorie-restricted (E) diets are associated with increased and reduced risk for colorectal cancer (CRC), respectively. Metabolomes associated with H- vs. E-associated CRC risk have never been directly compared, nor has how these diets influence proximal (PC), medial (MC), and distal (DC) colon metabolomes. Our objective was to elucidate metabolites associated with abberant crypt foci (ACF) (a marker of CRC risk) and consumption of H, E, or normocaloric control diet (C) in the PC, MC, and DC. C57BL/6N mice (3-weeks-old) consumed C, E, or H early diets. In weeks 16-21, animals received azoxymethane to induce ACF and switched to C, E, or H progression diets until week 60. Colon region extracts were analyzed using ultra-high-performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS). Metabolites associated with diet*ACF in each colon region were determined using: metabolite ~ ACF + early diet + progression diet + ACF*early diet + ACF*progression diet + cohort + weight. HILIC-HRMS analysis in positive and negative ionization mode detected 492 and 415 metabolites, respectively. Linear models revealed 21 metabolites significantly associated with early E diet*ACF (MC: 8, PC:13), 14 with early H diet*ACF (DC), 27 with progression H diet*ACF (DC: 14, MC: 2, PC: 11), and 20 with progression E diet*ACF (DC: 17, PC: 1, PC & DC: 1). Little to no overlap is observed between colon regions, revealing that the diet*ACF interaction is region-specific. Studies in humans will determine if these metabolites may serve as early biomarkers for CRC diagnosis.