The influence of light soaking and heat stress on the degradation of indium tin oxide (ITO)/CH3NH3SnI3 and SiO2/CH3NH3SnI3 hybrid perovskite is studied. The measurements of X-ray photoelectron survey spectra (XPS) showed an increase in the concentration of substrate ions in the surface layer of ITO/CH3NH3SnI3 and reduction of N:Sn and I:Sn ratios after 500 h of white light irradiation and 200 h of annealing at 90 °C. The high-energy-resolved XPS Sn three-dimensional (3d) spectra of ITO/CH3NH3SnI3 indicated a consistent increase in the contribution of Sn4+ ions at these exposure times under light soaking and heat stress. Scanning electron microscopy (SEM) measurements show a violation of the continuity of the perovskite layer with the exposure time and an increase in the size of the voids, which is consistent with the indicated changes in the XPS spectra. On the other hand, we consider the effect of irradiation and annealing on the diffusion of the substrate elements and their chemical interaction with the overlying perovskite layers. The XPS Sn 3d, O 1s, and valence band (VB) measurements and density functional theory (DFT) calculations reveal that at the initial stages of CH3NH3SnI3 degradation, the SnI4 phase separation occurs and with a further increase in exposure time, tin is oxidized to form a SnO2 phase. In addition, we found that CH3NH3SnI3 perovskite prepared on a SiO2 substrate is more stable than on an ITO substrate, and the effect of the oxidation of tin atoms due to the migration of oxygen ions is very weak. The theoretical modeling demonstrates that the formation of SnI2 defects in CH3NH3SnI3 became irreversible due to the oxidation by the migration of the oxygen ions from the substrate. The calculated formation energy of an oxygen vacancy in ITO is about 2 times smaller than in SiO2 that explains the instability of ITO/CH3NH3SnI3.