In order to design a suitable catalyst for hydrocracking (HCK) of vacuum residue (VR), a series of NiMoS/γ-Al2O3 catalysts were prepared with varying Mo loading amounts, Ni addition, P addition, and porosity of γ-Al2O3 support, and were applied for the VR HCK. Activity tests were conducted in an autoclave batch reactor at 693 K and 10 MPa H2 for the VR HCK in the presence of 0.26 wt% catalyst and 33.0 wt% tetralin. X-ray absorption spectroscopy (XAS), N2-physisorption, H2-temperature programmed reduction (H2-TPR), and energy dispersive X-ray fluorescence (ED-XRF) measurements were applied to verify the physical properties of the prepared catalysts. The amount of Mo loadings on γ-Al2O3 was observed most favorable at 8.0 wt% with the asphaltene conversion of 62.9%. The addition of Ni had minimal effect on the VR HCK, but the effect on the hydrodesulfurization (HDS) of VR was significant. It was noteworthy that the increase in porosity of the γ-Al2O3 support played an important role in enhancing the asphaltene conversion to 68.5%.