The CREB3 family of proteins, encompassing CREB3 and its four homologs (CREB3L1, CREB3L2, CREB3L3, and CREB3L4), exerts pivotal control over cellular protein metabolism in response to unfolded protein reactions. Under conditions of endoplasmic reticulum stress, activation of the CREB3 family occurs through regulated intramembrane proteolysis within the endoplasmic reticulum membrane. Perturbations in the function and expression of the CREB3 family have been closely associated with the development of diverse diseases, with a particular emphasis on cancer. Recent investigations have shed light on the indispensable role played by CREB3 family members in modulating the onset and progression of various human cancers. This comprehensive review endeavors to provide an in-depth examination of the involvement of CREB3 family members in distinct human cancer types, accentuating their significance in the pathogenesis of cancer and the manifestation of malignant phenotypes.