The strong metal-support interaction inducing combined effect plays a crucial role in the catalysis reaction. Herein, we revealed that the combined advantages of MoSe2, Ru, and hollow carbon spheres in the form of Ru nanoparticles (NPs) anchored on a two-dimensionally ordered MoSe2 nanosheet-embedded mesoporous hollow carbon spheres surface (Ru/MoSe2@MHCS) for the largely boosted hydrogen evolution reaction (HER) performance. The combined advantages from the conductive support, oxyphilic MoSe2, and Ru active sites imparted a strong synergistic effect and charge redistribution in the Ru periphery which induced high catalytic activity, stability, and kinetics for HER. Specifically, the obtained Ru/MoSe2@MHCS required a small overpotential of 25.5 and 38.4 mV to drive the kinetic current density of 10 mA cm−2 both in acid and alkaline media, respectively, which was comparable to that of the Pt/C catalyst. Experimental and theoretical results demonstrated that the charge transfer from MoSe2 to Ru NPs enriched the electronic density of Ru sites and thus facilitated hydrogen adsorption and water dissociation. The current work showed the significant interfacial engineering in Ru-based catalysts development and catalysis promotion effect understanding via the metal-support interaction.