Sputter-deposited Al/CuO multilayers capable of highly energetic reactions have been the subject of intense studies for tunable initiation and actuation. Designing high performance Al/CuO-based initiator devices definitively requires reliable prediction of their ignition and reaction kinetics including self-heating or aging as a function of heating rate and environmental conditions. The paper proposes a heterogeneous reaction model integrating an ensemble of basic mechanisms (oxygen diffusion, structural transformations, polymorphic phase changes) that have been collected from recent experimental investigations. The reaction model assumes that the rate of reaction is limited by the transport of oxygen across the growing layer of Al2O3 separating Al and CuO. Importantly, we show that the model predicts reasonably all exotherms through a wide range of temperature (ambient-1000 °C), all resulting from a pure diffusion process as experimentally observed for such Al/CuO multilayers. The model shows how the temperature ramp affects the structure of the multilayer and especially the growth of alumina-based interfacial regions. It highlights the importance of the interfacial chemistry evolution such as the native mixture of AlxCuyOz transformation into a thin amorphous alumina, and the polymorphic phase transformation of this latter. The first one occurring at ~350 °C results in a loss of continuity of the interface leading to the accelerated redox 2 reaction whereas the second one occurring between 500 and 600 °C produces a denser barrier to oxygen diffusion leading to the stop of redox reaction. We finally use the model to simulate thermal annealing as usually performed in accelerated aging experiments. We theoretically observe and experimentally validate that a two weeks exposure of the multilayers at 200 °C starts degrading the multilayers thermal properties whereas when the temperature remains below 200 °C, the material keeps its entire integrity.