Cu/SiO2 catalysts are prone to deactivation in the dimethyl oxalate (DMO) hydrogenation when high content of methyl glycolate (MG) is produced at a high weight hourly space velocity (WHSV). However, few research studies have focused on the deactivation mechanism, which has become the bottleneck for improving the efficiency of the syngas-to-ethylene glycol (EG) technology. Herein, the deactivation mechanism of copper-based catalysts in the synthesis of EG was studied with MG hydrogenation as the model reaction. The stability test results proved that carrier loss in the form of tetramethoxysilane (TMOS) during the reaction could destroy the structure of the catalysts to some extent. The aggregation of copper nanoparticles (NPs) was also one of the reasons for the deactivation. However, the major factor for the deactivation of the Cu/SiO2 catalyst was deduced to be carbon deposition. The weak acid-base sites of the catalyst led to some side reactions such as alcohol dehydration, condensation, and aromatization via the intermediate of glycolic aldehyde. Larger molecules were formed and accumulated in the pores of the catalyst, leading to the carbon deposition, which caused a rapid deactivation of the catalysts. This deactivation mechanism provides an important guide to develop a highly stable copper-based catalyst for the DMO hydrogenation to EG.