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Highlights • A large-scale of 15,488 EnergyPlus simulations for commercial buildings in the U.S. • Nationwide energy savings for a single and combinations of multiple ECMs. • Nationwide energy savings for the ECM of fault detection and diagnostics. Abstract Buildings consumed 40% of the energy in the United States, which is more than any other sectors of the U.S. economy, including transportation and industry. The majority of this energy was used for lighting, space heating, cooling, ventilation, and water heating in the buildings. It is well known that the carbon emission is proportional to the energy consumption. Enhancing building efficiency becomes one of the easiest, most immediate and most cost-effective ways to reduce carbon emissions. This paper focuses on the simulation-based nationwide energy savings analysis of different energy conservation measures (ECMs) to enhance building energy performance. The study includes 44 different ECMs, which were simulated in 16 different climate zones for 11 different commercial building types in the U.S. Simulations were conducted using a whole building simulation program, EnergyPlus. Commercial prototype building models from the U.S. Department of Energy [1] were used as the baselines. Model input files were automatically modified to incorporate with 44 different ECMs using scripts. The baselines were based on American Society of Heating, Refrigeration, and Air-conditioning Engineers (ASHRAE) [2] Standard 90.1 and International Energy Conservation Code (IECC). A total of 15,488 simulations were conducted to study the nationwide energy savings potentials. The details of these 44 proposed ECMs and their corresponding nationwide saving potentials are presented and discussed in this paper. [ABSTRACT FROM AUTHOR]