A significant boost to the catalytic technology of CO2-to-DME hydrogenation in a single step was recently given by the design of novel hybrid multimetallic/zeolite systems. However, a significant drop of catalyst activity after few hours of operation time pushes now the research interest towards the development of more stable multi-functional systems, suitable to ensure activity, selectivity and lifetime under typical industrial conditions. In this work, the influence of different home-made zeolite samples (i.e., Sil-1, MFI, Y, FER, BEA, MOR), integrated in a weight ratio of 1:1 with a CuO-ZnO-ZrO2 metal-oxide(s) phase, was investigated under long-term stability tests in a fixed bed reactor during CO2 hydrogenation reaction to assess the activity-selectivity pattern of the hybrid catalyst as well as their deactivation trend during operation time. The individuation of key structure-activity relationships helped to explain how the extent of interaction between the metal-oxides phase with the zeolite surface as well as the strength of the acid sites significantly control the catalyst stability.