The Ti-6Al-4V (TC4) alloy wheel hub has exhibited some defects that affect the properties during the vertical centrifugal casting process. Therefore, the analysis of the solidification process would contribute to solving the above-mentioned problems. In this study, an orthogonal experimental design was employed to optimize the process parameters (rotational speed, mold preheating temperature, and pouring temperature) of the vertical centrifugal casting method. The effects of process parameters on the velocity field, temperature field, and total shrinkage porosity during the solidification process were explored, and the microstructure and mechanical properties of the wheel hub prepared by the vertical centrifugal casting method were also investigated. The results showed that the rotational speed mainly induced the change of the velocity field. The pouring temperature and mold preheating temperature affected the temperature field and solidification time. Based on the analysis of the orthogonal experiment, the optimal parameters were confirmed as a rotational speed of 225 rpm, mold preheating temperature of 400 °C, and pouring temperature of 1750 °C, respectively. The simulation results of total shrinkage porosity were in agreement with the experiment results. The wheel hub was composed of nonuniform α and β phases. The lath α phase precipitated from larger β grains with different orientations. Compared with the other samples at different locations, the α phase in the PM sample (middle of the TC4 wheel hub) displayed high peak intensity and uniformly distributed β phase along the radial direction of the wheel hub. Moreover, the PM sample revealed a higher tensile strength of 820 MPa and similar Vickers hardness of 318 HV compared with the other samples at different locations, which were higher than those of rolling and extrusion molding. This experiment design would provide a good reference for the vertical centrifugal casting of the TC4 alloy.