Direct ascorbic acid fuel cells (DAAFCs) employ biocompatible ascorbic acid (AA) as fuel, allowing convenient storage, transportation, and fueling as well as avoiding fuel crossover. The AA oxidation reaction (AAOR) largely governs the performance of DAAFCs. However, AAOR electrocatalysts currently have low activity, and state-of-the-art ones are limited to carbon black. Herein, we report the synthesis of an unprecedented AAOR electrocatalyst comprising 3.9 ± 1.1 nm CeO2 nanoparticles evenly distributed on carbon black simply by the wet chemical precipitation of Ce(OH)3 and a subsequent heat treatment. The resultant CeO2/C shows a remarkable AAOR activity with a peak current density of 13.1 mA cm−2, which is 1.7 times of that of carbon black (7.67 mA cm−2). According to X-ray photoelectron spectroscopy (XPS), the surface Ce3+ of CeO2 appears to contribute to the AAOR activity. Furthermore, our density functional theory (DFT) calculation reveals that that the proton of the hydroxyl group of AA can easily migrate to the bridging O sites of CeO2, resulting in a faster AAOR with respect to the pristine carbon, -COOH, and -C=O sites of carbon. After an i-t test, CeO2/C loses 17.8% of its initial current density, which is much superior to that of carbon black. CeO2 can capture the electrons generated by the AAOR to protect the -COOH and -C=O sites from being reduced. Finally, DAAFCs fabricated with CeO2/C exhibit a remarkable power density of 41.3 mW cm−2, which is the highest among proton-exchange-membrane-based DAAFCs in the literature.