Fructose consumption is linked to the rising incidence of obesity and cancer, two of the leading causes of morbidity and mortality globally. The small intestine is the first organ to metabolize dietary fructose and it is bathed in the sugar following the ingestion of high-fructose corn syrup (HFCS) or sucrose, common sweeteners found in beverages and processed foods worldwide. In the intestinal epithelium, fructose is transported by GLUT5 and phosphorylated by ketohexokinase to form fructose 1-phosphate, which accumulates to high levels in the cell. While this pathway is implicated in obesity and tumor promotion, the exact mechanism driving these pathologies in the intestine remains unclear. Here, we show that dietary fructose promotes intestinal cell survival and increases intestinal villus length across multiple murine models. Increased villus length expands gut surface area and increases nutrient absorption and adiposity in mice fed a high-fat diet. In hypoxic intestinal cells, fructose 1-phosphate inhibits the M2 isoform of pyruvate kinase to promote cell survival. Genetic ablation of ketohexokinase or stimulation of pyruvate kinase prevents villus elongation and abolishes HFCS-promoted nutrient absorption and tumor growth. The ability of fructose to promote cell survival via an allosteric metabolite thus provides additional insight into Western-diet associated adiposity and a compelling explanation for HFCS-promoted tumor growth.