In response to the growing demand for clean energy development, hydrogen (H2) generation from liquid organic/inorganic hydrides has emerged as an innovative and sustainable alternative to fossil fuels. In this study, we report that Cu nanoclusters supported on porous CeO2 nanorods with modulated oxygen vacancies significantly enhance efficient H2 generation from a DMF-H2O system under mild conditions. Experimental results reveal that the increased oxygen vacancies in the porous CeO2 nanorods facilitate H2O dissociation and elevate the electron density of Cu, thereby promoting the decomposition of formate groups to release H2. Consequently, the optimized Cu/PN-CeO2-180 catalyst demonstrates an exceptional H2 generation rate of 0.55 molH2 molCu−1 h−1, which is 2.5 times higher than that of Cu/NR-CeO2. Both Experimental and DFT results suggest that abundant oxygen vacancies in CeO2 support tune the Cu/CeO2 interface to boost reaction activity. This study underscores a promising strategy for hydrogen production from liquid chemical hydrogen storage systems, offering a viable pathway toward sustainable energy solutions.