Cellulose is a cheap, ecofriendly, and abundant organic polymer. In this study, physically or chemically modified microcrystalline cellulose (MCC) was evaluated as a kinetic hydrate inhibitor (KHI) for CH4 hydrates using experimental and computational methods. To overcome the strong hydrophobicity of MCC, high-pressure homogenized cellulose (HPHC) was prepared by dispersing MCC homogeneously in water, and surface-modified ionic cellulose (SMIC) was obtained by attaching an ionic liquid (1,3-dimethylimidazolium methylphosphite, [DMIM][MP]) to the surface of MCC. The onset temperature and gas uptake of CH4 hydrates were experimentally measured to examine the inhibition performance of HPHC and SMIC. Experimental results demonstrated that both HPHC and SMIC functioned as potential KHIs and SMIC had better inhibition capability than HPHC. Molecular dynamics simulations were performed to reveal the inhibition mechanisms of the KHIs during cage formation and hydrate growth. It was found that the different inhibition effects of the KHIs were caused by a combination of multiple inhibition mechanisms, including both their interactions with water and cage adsorption. Given the improved hydrophilicity and inhibition performance through physical or chemical modification of the naturally derived organic compound, cellulose holds great potential as a novel and green KHI.