Our data suggest that (a) high TRAP1 expression correlates with enhancement of Warburg metabolism in human CRC samples, patient‐derived spheroids, and cell lines; (b) TRAP1 control of glycolysis depends on its interaction with PFK1 on endoplasmic reticulum with regulation of PFK1 activity/stability; and (c) TRAP1 modulates glycolysis and PFK1 activity to balance modifications of mitochondrial respiration. Here, TRAP1 is linked to colorectal carcinoma.