The deactivation of the nanosized Fe₂O₃-Al₂O₃ and CuO-MgO catalysts prepared by simply hand mixing the active oxide with the support/diluter was studied during the CO oxidation. It is shown that a difference in the catalytic activity of nanosystems characterized by the same nanoparticle size of the active component is associated with the agglomeration caused by conditions of the catalyst preparation. The decrease in the active component surface with an increase in heating temperature from 300 °C to 400 °C does not affect the size of the iron oxide nanoparticles. However, it causes their agglomeration accompanied by a decrease in the CO oxidation rate. A strong deactivating effect of the mechanochemical treatment on the catalytic activity of the CuO-MgO mixed solids was found. The effect is associated with the morphological changes in the mechanochemically treated structures, particularly, the disappearance of the grain boundaries caused by the agglomeration of CuO nanoparticles. Influence of the crystal structure, nanoparticle size, agglomeration degree, and metal oxide-support/diluter interaction on the catalytic activity was analyzed based on X-ray diffraction (XRD), transmission electron microscopy (TEM), and Brunauer-Emmett-Teller (BET) surface area studies. Our results reveal that agglomeration may have significant effect on the functional properties of the copper- and iron oxide-containing catalysts whose catalytic activity is mainly associated with the size of nanoparticles in the solid.