<p>Natural gas hydrates (NGHs) offer significant potential for energy recovery and carbon sequestration, yet the thermal stability of polycrystalline CH₄-CO₂ hydrates (PCCHs) which is critical for CO₂-based NGH exploitation, remains poorly understood. Here, we unravel CO₂’s role in reshaping the thermal dissociation behaviors of PCCHs via high-throughput molecular dynamics (MD) simulations and machine learning (ML). We demonstrate that CO₂ reduces the stability of PCCHs, with a 20% increase in CO₂ concentration lowering the melting point by approximately 6 K. Microstructural analysis reveals that this destabilization arises from CO₂-induced distortion of 5¹² cage and formation of unconventional metastable cages. Thermal dissociation occurs via cage transformations and dissociations, where 4¹5¹⁰6² and 5¹²6² cages act as hubs for solid–solid restructuring pathway. Crucially, CH₄ guest molecules facilitate simpler, faster cage transformations than CO₂, which requires complex rearrangements. We further develop a GBDT ML model that accurately predicts PCCH melting points using microstructural information, identifying 5¹², 5¹²6², and 5¹⁰6³ cages as key predictors. This model provides a practical tool for guiding CO₂-based NGH exploitation and designing hydrate storage systems. These insights advance the molecular-level understanding of hydrate stability for CO₂ sequestration and NGH recovery.</p> Graphical Abstract <p></p>