Metal nanoparticles with a precisely controlled particle size distribution are ideal model catalysts for fundamental studies in catalysis. In this work, the thermal stability of size-selected Cu nanoparticles (Cu NPs) were deposited by magnetron sputtering, and their thermal stability was investigated using transmission electron microscopy and X-ray photoelectron spectroscopy. The influence of particle size, support, temperature, as well as CO2 hydrogenation atmosphere was systematically studied. We found that at 220 °C in ultra-high vacuum (UHV), carbon-supported 4 nm Cu NPs sintered through particle migration while the 8 nm Cu NPs were relatively stable. As the temperature increased to 320 and 460 °C, both samples sintered severely, and Ostwald ripening was suggested to be the dominant mechanism. In addition, we observed that SiO2 support can better stabilize Cu NPs upon heat treatment under both UHV and CO2 hydrogenation atmosphere (1 mbar of 1:1 CO2/H2 mixture), due to the stronger interaction between SiO2 and Cu compared to that between carbon and Cu. Furthermore, under a CO2 hydrogenation atmosphere, the stability of Cu NPs is suggested to be influenced by the interplay of redispersion, agglomeration, and volatilization. These findings from model systems can offer new insights for understanding the deactivation of Cu-based catalysts.