Using both in vitro and in vivo models, including a colonocyte‐specific CRABP2 conditional knockout mouse model (Crabp2ΔIEC) and a subcutaneous tumorigenesis assay in BALB/c nude mice, it is shown that nuclear CRABP2 enhances tumor growth by interacting with and downregulating the tumor suppressor RB1, whereas cytoplasmic CRABP2 suppresses CRC liver metastasis by interacting with AFG3L2 and promoting mitophagy. Here, RB1 is linked to neoplasm.