This article presents a novel strategy to prepare alumina-supported Mo and MoNi hydrodesulfurization (HDS) catalysts using Mo-based inorganic–organic hybrid nanocrystals (HNCs) as a superior precursor under moderate hydrothermal conditions. The characterization results revealed that each HNC in the aqueous solution has a size of ca. 2.5 nm and shows a core–shell structure with one Mo₈O₂₆⁴⁻ as the inorganic core and long-chain quaternary ammonium cations as the organic shell. The proposed approach not only significantly promotes the dispersion of supported Mo species, but also greatly enhances the stacking of MoS₂ active phase, endowing the resulting catalysts with sufficient and accessible Ni–Mo–S active sites and thereby with a remarkably enhanced HDS performance as compared to their counterparts prepared by the conventional impregnation method. Thereby, a novel precursor for preparing Mo-based catalysts was successfully developed and the roles of the HNC-derived preparation method in tuning the size and morphology of supported metal sulfide nanoparticles in HDS catalysts were demonstrated, shedding a light on the rational design and controllable fabrication of supported metal sulfide catalysts.