Mesoscale simulations of the shock-compression response of nickel and aluminum powder mixtures have been performed to investigate the influence of particle configuration (size, shape and distribution) on the micromechanical processes of deformation, mass flow and mixing. Real microstructures were constructed from scanning electron microscopy montages of the starting mixtures pre-pressed at various densities [Eakins D, Thadhani NN, J Appl Phys, 2007;101:043508]. The travel of the high-pressure disturbance was used to determine the equation-of-state of the mixture material, and compared to the results of real-time experiments for validation. Observations of particle-level processes were used to formulate an understanding of the wide range of macroscopic behaviors exhibited as a function of particle morphology and distribution, porosity, and dissimilarities in properties of the two constituents. The results reveal the effects of particle heterogeneity on the physical, chemical and micromechanical response of shock-compressed Ni + Al powder mixtures, and their role in the initiation of shock-induced chemical reactions.