Mn-Ce mixed oxides-supported Ru nanoparticles (Ru/MnXCe1OY) with enhanced oxygen mobility and strong metal-support interaction were prepared and applied to the aerobic oxidation of 5-hydroxymethylfurfural (HMF) to 2,5-furandicarboxylic acid (FDCA) without addition of any base additives. Oxygen and water were used as green oxidant and solvent, respectively. The catalysts were characterized in depth by XRD, H2-TPR, O2-TPD, UV–Vis DRS, XPS and TEM, to reveal materials properties from bulk to surface. The influence of Mn/Ce molar ratios in support materials and reaction parameters (i.e., HMF/Ru ratio, O2 pressure, reaction temperature and time) was systematically studied and optimized. The reaction route and rate-determining step for oxidation of HMF to FDCA over the Ru/MnXCe1OY catalysts were investigated by kinetic analysis. Well-dispersed metallic Ru nanoparticles with a mean size of 4.4 nm deposited on the support were found essential to activate and oxidize the HMF molecule. The Mn/Ce molar ratio was found to affect not only conversion of HMF but also distribution of products. The Ru/Mn6Ce1OY catalyst demonstrated an exceptional yield (≥99%) of FDCA, which corresponds in our conditions to one of the best productivity (5.3 molFDCA·molRu−1·h−1) ever reported in literature. The superior activity of the Ru/Mn6Ce1OY catalyst was mainly associated with (i) the strong metal-support interaction and (ii) the synergistic effect between manganese and cerium oxides. This catalyst showed the highest surface concentrations in Mn4+ and Ce3+ among the series, which, as a consequence, enhanced the availability and mobility of active oxygen species. This catalyst was shown resistant to deactivation during eight recycling uses thanks to a strong metal-support interaction between Ru nanoparticles and the Mn-Ce mixed oxide used as a support.