A mathematical model was built using a new macrokinetic theory to investigate the mechanical treatment and two-step mechanochemical synthesis of inorganic substances in the mode of layer-by-layer combustion. Powders (SnO2, NiCrAl, Cu) and powder mixtures (SnO2 + Al, SnO2 + Si, Ti + Ni, Nb + Si) were used. The proposed macroscopic mathematical model expands the understanding of the macrokinetics of mechanochemical synthesis and identifies and classifies its mechanisms. The effect of mechanochemical pre-treatment on the mechanosynthesis of final products was taken into account by introducing the multidirectional parameters, such as structural (formation of the interfacial surface), kinetic (defect formation) and temperature factors, initial mechanochemical transformations, and formation of inert material due to the abrasion of milling tools. The inverse problem methods were proposed to determine the kinetic constants describing initial mechanochemical transformations and abrasion during mechanical activation.