The success of natural gas hydrate (NGH) production test in 2020 at the South China Sea suggests that horizontal wells have the potential to enhance the productivity of low-permeability NGH reservoirs. However, the vertical location of the horizontal well can significantly impact gas production and reservoir mechanical response, with additional uncertainties in multilayer reservoirs. Based on geological data from W17 deposit in the South China Sea, this study conducts a numerical analysis on the impact of well location during depressurization production of a multilayer NGH reservoir by horizontal well. And the productionsubsidence performance index (PSPI) is introduced for quantitative evaluation of the production performance under the combined consideration of natural gas production and seafloor subsidence.The results indicate that, first, the highest gas production rate is observed in case F-1 [well location at the top of the free-gas layer (FGL)] in the initial stage and in case H-4 [well location at the lower middle of the hydrate-bearing layer (HBL)] in the later stage, which is 4.01 × 10 4 and 0.24 × 10 4 m 3 •day −1 , respectively. Second, when the well location is at the top of HBL, an earlier disappearance of the low-permeability barrier brought by the solid hydrate filling leads to the faster water production and reservoir pressure drop, which further contributes to the seafloor subsidence. Finally, when the weights of normalized subsidence (1 − N S ) and normalized cumulative gas production (N P ) are equal, after 3000 days of production, the well location at the bottom of the HBL (case H-5) performs the best, achieving a PSPI of 0.82, whereas the well location at the top of the HBL (case H-1) performs the poorest, with a PSPI of only 0.20. This study can provide a reference for the vertical location of horizontal wells during depressurization of multilayer NGH reservoirs.