Natural gas hydrates are one of very important future clean energy resources with extensive distribution in the world. The field production tests are very difficult with high investment, while numerical simulation is an effective and economical method for the early evaluation. HydrateBiot, a novel thermo-hydro-mechanical (THM) coupled simulator, has been developed to investigate the mechanical behaviors during gas production from hydrate reservoirs. For the clayey-silt hydrate reservoirs in the Shenhu area of South China Sea, the horizontal well was proposed for improving gas production through depressurization. The controllable parameters, including well placement and well perforation length, were optimized firstly. HydrateBiot was used to predict the mechanical responses induced by gas production from hydrate reservoirs. The results indicated that the horizontal well placement significantly affected hydrate production efficiency. Thus, the advanced technology, such as hydrate reservoir precise exploration and offshore directional drilling, should be developed in the future. When the horizontal well length exceeded 400 m, the increase in well length led to a slight decrease in hydrate production efficiency. The mechanical responses suggested that depressurization led to stress concentration and increased in shear stress around the horizontal well. The subsidence mainly derived from compression of pore volume in sediments during depressurization. The maximum seafloor subsidence reached approximately 0.5 m after 1-year depressurization using horizontal well. The potential shear failure in the hydrate reservoir was mainly due to significant increase in shear stress and hydrate dissociation for weakening sediments. Thus, a balance between mechanical stability and gas productivity must be considered during depressurization by using horizontal well. The developed methods and obtained results presented here could help engineers to design safe hydrate production schemes under similar reservoir conditions and to conclude the complex mechanical behaviors during depressurization hydrate production.