CeO with the reversible Ce/Ce redox pair exhibits multiple enzyme-like catalytic performance, which has been recognized as a promising nanozyme with potentials for disease diagnosis and treatments. Tailorable surface physicochemical properties of various CeO catalysts with controllable sizes, morphologies, and surface states enable a rich surface chemistry for their interactions with various molecules and species, thus delivering a wide variety of catalytic behaviors under different conditions. Despite the significant progress made in developing CeO-based nanozymes and their explorations for practical applications, their catalytic activity and specificity are still uncompetitive to their counterparts of natural enzymes under physiological environments. With the attempt to provide the insights on the rational design of highly performed CeO nanozymes, this review focuses on the recent explorations on the catalytic mechanisms of CeO with multiple enzyme-like performance. Given the detailed discussion and proposed perspectives, we hope this review can raise more interest and stimulate more efforts on this multi-disciplinary field.