This study explored the fully coupled thermo-hydro-chemical response of natural gas hydrate (NGH) recovery, where the factors considered are that the hydrate decomposes from solid to methane and water, two-phase flow, and heat transfer. The fully coupled numerical model developed was verified by matching the data of gas production and temperature that are collected from Masuda's experiment and then applied to simulate the NGH field trial. The simulation result showed that both the model (H-2-C) ignoring heat transfer and the model (H-1-C) ignoring two-phase flow overestimated the production of NGH, and there were obvious interfaces in evolution curves of reservoir properties. Sensitivity analysis showed that the peak gas production rate and cumulative gas production increased with the increase of the production pressure difference, initial absolute permeability, and phase equilibrium parameter e(1) and decreased along with the increasing of the initial water saturation. The hydrate phase equilibrium conditions and the wellhole pressure enhanced the decomposition rate of the hydrate by changing the difference between equilibrium pressure and reservoir pressure. The initial absolute permeability and water saturation affected the hydrate depressurization by changing the gas flow capacity in the reservoir. Therefore, the gas production will be effective in the future NGH commercial exploitation if the proper enhancement of pressure difference and that of the gas flow capacity can be combined.