In order to design a suitable catalyst for hydrocracking (HCK) of vacuum residue (VR), a series of NiMoS/gamma-Al2O3 catalysts were prepared with varying Mo loading amounts, Ni addition, P addition, and porosity of gamma-Al2O3 support, and were applied for the VR HCK. Activity tests were conducted in an autoclave batch reactor at 693 K and 10 MPa H-2 for the VR HCK in the presence of 0.26 wt% catalyst and 33.0 wt% tetralin. X-ray absorption spectroscopy (XAS), N-2-physisorption, H-2-temperature programmed reduction (H-2-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 gamma-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 hydro-desulfurization (HDS) of VR was significant. It was noteworthy that the increase in porosity of the gamma-Al2O3 support played an important role in enhancing the asphaltene conversion to 68.5%.