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In this study, the thermal decomposition of glimepiride, a common antidiabetic drug, was analyzed in the presence of N2 and O2 and various metal oxide catalysts. The analysis was conducted using TGA. The results showed that there were two significant mass losses in the presence of N2, that correspond to thermal decomposition of the drug. When N2 was replaced by O2, an additional mass loss was observed that corresponds to the oxidation of the drug at higher temperature. Density functional theory was implemented to explain the thermo-oxidative decomposition of the drug. The isoconversional method was also used to deduce the activation energies of the process. Upon all catalysts used, vanadium oxide was the most efficient in lowering the temperature required for thermal decomposition. The results of this study pave way for future work into purifying wastewater from pharmaceuticals via adsorption using metal oxides catalysts.