Abstract Methane hydrate (MH) is regarded as one of the potential and substantial energy resources. The permeability of hydrate-bearing layer (HBL) can potentially influence heat and mass transfer during hydrate dissociation by depressurization. In this study, a reservoir-scale MH model was constructed to investigate the effect of permeability anisotropy on gas production behaviors by depressurization with a horizontal well. The numerical results indicate that permeability anisotropy can initially negatively influence the hydrate dissociation and gas production, but later promote the process. Meanwhile, permeability anisotropy can lead to an increase of ratio of gas phase to total production and gas-to-water ratio during long-term gas production. Moreover, permeability anisotropy can enhance the horizontal flow and the dissociation reaction in the top part of the HBL for a long period, but also leads to an increase of accumulated free gas in the reservoir. Furthermore, the comparison of horizontal well production and vertical well production indicates that the horizontal well can increase the gas production by one order of magnitude than that of vertical well during a production period of 360 days, and permeability anisotropy appears to have less effect on gas production in the initial short stage when using the vertical well.