One of the major anthropogenic sources of greenhouse gases is the operation of building stock. Improving its energy efficiency has the potential to significantly contribute to achieving climate change mitigation targets. The purpose of this study was to roughly estimate such potential for the operation of the national building stock of Czechia to steer the national debate on the development of related national plans. The estimation is based on a simplified energy model of the Czech building stock that consists of sub-models of residential and nonresidential building stocks, for which their future energy consumptions, shares of energy carriers and sources, and emission factors were modeled in four scenarios. Uncertainties from the approximation of the emission factors were investigated in a sensitivity analysis. The results showed that the operation of the Czech building stock in 2016 totaled 36.9 Mt CO2, which represented 34.6% of the total national carbon dioxide emissions. The four building stock scenarios could produce reductions in the carbon dioxide emissions of between 28% and 93% by 2050, when also considering on-side production from photovoltaics. The implementation of the most ambitious scenario would represent a drop in national CO2 yearly emissions by 43.2% by 2050 (compared to 2016).