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Simple Summary: One of the hallmarks of cancer is the deregulation of cellular metabolism. The study investigates the potency of the administration of beta-hydroxybutyrate (BOHB) to elevate oxaliplatin's cytotoxic effect in colorectal cancer. The study employed an in vitro organoid model to assess this dual treatment. The results exhibited that non-toxic doses (7.5 and 10mM) of BOHB with oxaliplatin treatment significantly increased the cytotoxic effect of oxaliplatin in colorectal cancer organoids by altering energy metabolism, leading to higher levels of reactive oxygen species (ROS). Opposingly, healthy colon organoids were not affected by the dual treatment as in colorectal cancer organoids. Melatonin was found to neutralize this effect by protecting cancer cells from oxidative stress. The study suggests that BOHB may improve the effectiveness of chemotherapy, particularly with drugs that have a similar mechanism of action to oxaliplatin, in treating colorectal cancer, potentially leading to better outcomes for patients. Deregulation of cellular metabolism has recently emerged as a notable cancer characteristic. This reprogramming of key metabolic pathways supports tumor growth. Targeting cancer metabolism demonstrates the potential for managing colorectal cancer. Beta-hydroxybutyrate (BOHB) acts as an acetyl-CoA source for the tricarboxylic acid (TCA) cycle, possibly redirecting energy metabolic pathways towards the TCA cycle that could enhance sensitivity to oxaliplatin, through the generation of reactive oxygen species (ROS). This study explores the potential of BOHB to enhance oxaliplatin's cytotoxic effect by altering the energy metabolism in colorectal cancer. The study employed advanced in vitro organoid technology, which successfully emulates in vivo physiology. The combination treatment efficacy of BOHB and oxaliplatin was evaluated via cell viability assay. The levels of key proteins involved in energy metabolism, apoptotic pathways, DNA damage markers, and histone acetylation were analyzed via Western Blot. ROS levels were evaluated via flow cytometer. Non-toxic doses of BOHB with oxaliplatin significantly amplified cytotoxicity in colorectal cancer organoids. Treatment with BOHB and/or melatonin resulted in significantly decreased lactate dehydrogenase A and increased mitochondrial carrier protein 2 levels, indicating inhibited aerobic glycolysis and an increased oxidative phosphorylation rate. This metabolic shift induced apoptotic cell death mediated by oxaliplatin, owing to high levels of ROS. Melatonin counteracted this effect by protecting cancer cells from high oxidative stress conditions. BOHB may enhance the efficacy of chemotherapeutics with a similar mechanism of action to oxaliplatin in colorectal cancer treatment. These innovative combinations could improve treatment outcomes for colorectal cancer patients. [ABSTRACT FROM AUTHOR]