Structural parameters play a decisive role in the performance of hydrocyclones for in situ natural gas hydrate (NGH) recovery and desanding. In this paper, the effects of key structural parameters on its performance were investigated by numerical simulations and experimental methods. The results show that the most influential factors are the spiral pitch of the spiral inlet, the vortex finder diameter, and the spigot diameter. The second most influential factors are the spiral turn number and the cone angle. Other parameters have the least influence. Specifically, the NGH recovery efficiency and pressure drop increase, but desanding efficiency decreases as d 0 /D and the cone angle increase. The NGH recovery efficiency and pressure drop decrease and desanding efficiency increases as d s /D increases. Therefore, it is necessary to choose a suitable value to balance the efficiency and pressure drop to improve the performance, for example, selecting the appropriate diameter ratio of the vortex finder and spigot. The above results can be used for the engineering design of in situ separators in marine hydrate mining and further realize in situ desanding, NGH recovery, and sand backfilling.