Natural gas hydrates (NGHs) buried in the Shenhu area are characterized by fine-grained sediments with interbedded hydrate-free layers. However, few is known about the influence of hydrate-free interlayers (HFIs) on gas production, which may control efficient and safe gas recovery from NGH reservoirs in long-term production. In this study, a field-data-based heterogeneous reservoir model is established to evaluate gas production behavior of Shenhu NGH reservoir with HFIs during depressurization. We compare the gas production from the hydrate reservoir with different HFIs characteristics. In a vertical well configuration, NGHs adjacent to HFIs dissociate preferentially over time, thereby significantly increasing average methane production and gas-to-water ratio. Notably, highly permeable HFIs (especially those near the permeable underburden), which can be regarded as high-permeability channels, increase pressure diffusion and then fluid flow, heat transfer and long-term gas production efficiency. The interlayers provide a better pathway for gas migration and secondary hydrates form inhomogeneously in the dissociation front. In contrast, low-permeability HFIs can negatively affect gas production and decrease average gas production amount by nearly 32.4% at most. The HFIs with low permeability are unfavorable for fluid migration and convective heat transfer from the burdens. Under the same initial conditions, the alternative of single horizontal well promotes the gas extraction volume limitedly. This study suggests that the vertical well configuration may provide more promising gas production efficiency than that of the horizontal one for the heterogeneous NGH reservoirs with HFIs in vertical direction. Our finding can provide a useful guide for gas production strategy in NGH reservoirs with HFIs.