High-entropy alloys (HEAs) have been intensively pursued as potentially advanced materials because of their exceptional properties. However, the facile fabrication of nanometer-sized HEAs over conventional catalyst supports remains challenging, and the design of rational synthetic protocols would permit the development of innovative catalysts with a wide range of potential compositions. Herein, we demonstrate that titanium dioxide (TiO2) is a promising platform for the low-temperature synthesis of supported CoNiCuRuPd HEA nanoparticles (NPs) at 400°C. This process is driven by the pronounced hydrogen spillover effect on TiO2 in conjunction with coupled proton/electron transfer. In this process, Pd nuclei generated in the early stage act as uptake sites to enhance the migration of active hydrogen atoms, and the five component metals are simultaneously reduced by spilled hydrogen on the support rather than via direct reduction by gaseous H2. The CoNiCuRuPd HEA NPs on TiO2 produced in this work were found to be both active and extremely durable during the CO2 hydrogenation reaction. Characterization by means of various in situ techniques and theoretical calculations elucidated the specific mechanism by which the HEA NPs were formed and also established that a synergistic effect was obtained from this combination of elements.