Nanoscaled mesoporous silicas (NMS) with tunable mesostructure and morphology were successfully fabricated using a simple modified-Stöber synthesis system. The Al modified NMS-x materials with highly ordered mesostructures were used as supports to prepare hydrodesulfurization (HDS) catalysts NiMo/Al-NMS-x. The characteristics and activity test results revealed that the dispersion and morphology of NiMoS active phases were modulated on various supports, and TOF values showed dependence on the stacking degrees and dispersion of MoS2 slabs. Moreover, diffusion properties reflected that a support with larger pore size and 3D mesochannel would alleviate restrictive diffusion. Compared to other catalysts, NiMo/Al-NMS-7 with 3D cubic mesochannel and sphere-like shape exhibited the highest catalytic activity, i.e., HDS efficiency (95%, WHSV = 20 h−1), TOF (4.8 ± 0.32 h−1), rate constant (1.4 × 10-3 mol·g−1·h−1) and De (12.8 × 106 cm2·s−1), which would be derived from the preferable diffusion performance of guest-species, especially the better dispersion and suitable stacks of active phases.