This dataset supports a multiplexed hydrogen-deuterium exchange mass spectrometry (mHDX-MS) study investigating protein energy landscapes across hundreds of protein domains. Proteins continuously fluctuate between their native states and higher-energy conformations that influence stability, interactions, aggregation, and immunogenicity. However, these excited states remain difficult to characterize experimentally, limiting the development of predictive models for conformational energy landscapes. These data provide a foundation for machine learning approaches to predict protein energy landscapes and enhance biophysical modeling of protein folding and conformational dynamics.