Colorectal cancer (CRC) tends to occur at older age; however, CRC incidence rates have been rising sharply among young age groups. The increasing prevalence of obesity is recognized as a major risk, yet the mechanistic underpinnings remain poorly understood. Using a diet-induced obesity mouse model, we identified obesity-associated molecular changes in the colonic epithelium of young and aged mice, and we further investigated whether the changes were reversed after weight loss. Transcriptome analysis indicated that obesity-related colonic cellular metabolic switch favoring long-chain fatty acid oxidation happened in young mice, while obesity-associated downregulation of negative feedback regulators of pro-proliferative signaling pathways occurred in older mice. Strikingly, colonic DNA methylome was pre-programmed by obesity at young age, priming for a tumor-prone gene signature after aging. Furthermore, obesity-related changes were substantially preserved after short-term weight loss, but they were largely reversed after long-term weight loss. We provided mechanistic insights into increased CRC risk in obesity. Display omitted •Obesity reprograms mouse colonic DNA methylome, leading to gene expression changes•Obesity triggers a metabolic switch favoring long-chain fatty acids at young age•Obesity induces a tumor-prone gene signature in the colonic epithelium after aging•Obesity-related changes are reversed after long-term, but not short-term, weight loss Li et al. find that obesity-induced DNA methylation changes reprogram the colonic transcriptome, leading to a metabolic switch favoring long-chain fatty acid oxidation in young mice and a more tumor-prone gene signature after aging. Obesity-related changes are substantially preserved after short-term weight loss, but they are largely reversed after long-term weight loss.