CeO2 supported with Ni nanoparticles has emerged as a promising catalyst for enhancing the efficiency of dry reforming of methane (DRM) reaction. Methane dissociation (CH4 → CH3 + H) was reported as one of the rate-determining steps in the DRM reaction. We elucidated the reaction mechanism and explored methods for reducing the activation energy using density functional theory (DFT) calculations, where the activation energy of methane dissociation was determined at multiple Ni4 cluster sites on CeO2. In parallel, we experimentally evaluated methane dissociation based on the methane consumption rate in the DRM reaction using newly developed flower-like Ni-supported CeO2 catalyst (Ce(F)). The experimental activation energy was determined to be 0.69 eV (15.91 kcal mol-1), closely matching the DFT-calculated value of 0.80 eV (18.45 kcal mol-1) for the Ni4 cluster model, validating our theoretical predictions. Additionally, we discovered that positively charging the Ni4 can lower the activation energy of methane dissociation. These findings contribute to a deeper understanding of how to control the activation energy of the methane dissociation reaction in DRM.