<p>Natural gas hydrates represent a vast potential clean energy resource, and the CO₂/CH₄ replacement technique offers a promising strategy for their exploitation while enabling CO₂ sequestration. However, the underlying replacement mechanism, particularly how CO₂ enters the hydrate interior, remains unclear. Here, by employing microcanonical ensemble molecular dynamics simulations that inherently conserve the exothermic heat of replacement, a key physical aspect artificially dissipated in previous simulated ensembles, we investigated CO₂/CH₄ replacement behaviors in monocrystalline and polycrystalline CH₄ hydrates. Our results demonstrate that grain boundaries (GBs) play a critical role in facilitating the CO₂/CH₄ replacement process. GBs act as permanent active pathways, allowing CO₂ to penetrate deeply into the hydrate interior and sustaining the replacement. This process is driven by the abundance of non-standard cages within GBs, which exhibit transient lifetimes and higher molecular diffusivity. Furthermore, a cage transition analysis uncovers the cage transition pathways, indicating that large, mixed guest cages serve as intermediates during the conversion from CH₄-filled to CO₂-filled cages. These findings establish a “grain boundary diffusion and replacement” mechanism for CO₂/CH₄ replacement in gas hydrates, underscoring the crucial influence of microstructural defects on hydrate reactivity and replacement efficiency.</p>