The reactivity of heterogeneous energetic materials (HEMs) intimately depends on the underlying microstructural effects. For reactive materials, key factors include the microstructure distribution, morphology, size scale of heterogeneities, reactant mixing, and chemical kinetics of the reactants. We report the development of a mesoscale model for simulating the evolutions of the hotspot field and associated reaction processes when such materials are exposed to external excitations. The model explicitly accounts for microstructure, interdiffusion between the reactant species, advection of the species mixture, and chemical kinetics of the reaction. An Arrhenius relation is used to capture the rate of reactive heat release. The particular material analyzed is a composite of poly(vinylidene fluoride-co-trifluoroethylene) and nanoaluminum [or P(VDF-TrFE)/nAl]. The excitation leading to the initial microstructural temperature increase that kicks off the exothermic reactive processes is the dissipative heating arising from dielectric breakdown under the electric field developed through piezoelectricity and flexoelectricity of P(VDF-TrFE). As such, the model resolves both the breakdown process and the diffusion, advection, and exothermic reaction processes. The evolutions of the temperature and species distribution fields under the combined effects of breakdown and chemistry are used to predict the effects of microstructure, diffusion, and kinetics on several key metrics characterizing the reactive responses of the material. This mesoscale framework admits the quantification of uncertainties in these predicted macroscopic behavior measures due to microstructure heterogeneity fluctuations through the use of multiple, random but statistically equivalent microstructure instantiations. Although the particular hotspot inducing mechanism considered is dielectric breakdown here, the framework can be adapted to analyze reaction initiation and propagation and establish microstructure–reaction behavior relations under other types of hotspot inducing mechanisms, such as thermomechanical inelastic dissipation, frictional heating, and laser or microwave excitation.