The dependence of cancer cells on mitochondrial metabolism has been revealed in various cancer types. However, the mechanisms underlying this metabolic remodeling remain largely unclear. Solute carrier family 44 member 4 (SLC44A2) is a mitochondrial membrane-localized transmembrane protein belonging to the choline transporter-like protein family. Recently, it was reported that deletion of SLC44A2 impairs adhesion and increases proliferation in cultured lung mesenchymal cells. This finding implies that SLC44A2 may play a role in the malignant phenotypes of human cancers. However, the effects of SLC44A2 on malignant phenotypes and mitochondrial metabolism in human cancers remain unexplored. In the present investigation, we observed a significant reduction in SLC44A2 expression in colorectal cancer (CRC), and low SLC44A2 expression was closely associated with poorer survival of CRC patients. Functional assays demonstrated that SLC44A2 suppressed CRC growth and metastasis both in vitro and in vivo. Mechanistically, SLC44A2 inhibits mitochondrial fatty acid oxidation, thereby reducing energy supply and increase ROS stress. This effect is achieved by promoting mitochondrial E3 ubiquitin ligase 1 (MUL1)-regulated degradation of carnitine palmitoyltransferase 2 (CPT2) via enhancing the interaction between MUL1 and CPT2, without increasing MUL1 expression, which ultimately contributes to the proliferation and metastasis of CRC. Together, SLC44A2 functions as a critical tumor suppressor in CRC and potential therapeutic target in the treatment of this malignancy.