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A numerical model is established based on the plasticity theory and a thermomechanical coupled finite element method (FEM) to simulate the hot isostatic pressing (HIP) process of atomized and milled Ti6Al4V powders and is then experimentally verified. Key material parameters related to the simulation are obtained by experimental and calculation methods. The HIP densification mechanism for two types of Ti6Al4V powders are clarified through the analysis of the powder flow and relative density distribution of compacts using the proposed model. The results indicate that the densification trends of the two powders are not much different under the same working conditions and that milled powder with a higher energy is more conducive to densification and can better overcome the “corner effect” compared to atomized powder. The equiaxed microstructure of the milled powder sintered body contributes to increasing its strength, whereas the lamellar microstructure of the atomized powder sintered body contributes to increasing its plasticity.