The commercial development of natural gas hydrates (NGH) is important for addressing the future energy requirements due to the depletion of conventional sources. Analyzing and understanding the effectiveness of different production methods under various well configurations are essential for the exploitation of NGH. According to the typical physical properties of hydrate reservoirs in the South China Sea, a simulation model was established. The natural gas production behavior was compared and analyzed via one-time rapid depressurization and stepwise depressurization using a horizontal well. The results showed that the heat and mass transfer capacities in a horizontal well configuration are enhanced due to gravity, and the water yield is decreased. For a horizontal well, stepwise depressurization is more advantageous than the one-time rapid depressurization method. Stepwise depressurization can significantly reduce water production and increase external energy input, which heats up the reservoir quickly. In addition, the horizontal well configuration with stepwise depressurization has a wider application range and can be used in various hydrate reservoirs with different physical properties. Although the average gas production rate during stepwise depressurization with a horizontal well configuration is lower, the gas−water ratio, thermal efficiency, and comprehensive exploitation economy are higher.