Aiming at the separation of mud and sand in natural gas hydrate, for the designed built-in twisted tape hydrocyclone, the numerical simulation method was used to study the effects of different types of built-in twisted tape and operating conditions on the internal flow field of the hydrocyclone, separation efficiency, and influence of hydrate particle size distribution. The research results show that the built-in twisted tape has the same swirling direction as the hydrocyclone, which is beneficial to improving the swirling intensity, and the ability to carry and separate solid particles is obviously enhanced. The built-in twisted tape hydrocyclone with a length of 300 mm has better separation efficiency and internal flow field stability. By changing the conditions of the inlet velocity and the initial concentration of hydrate particles, the comparison shows that when the inlet velocity is 8 m/ s, the volume of mud and sand is 25%, the initial concentration of hydrate particles is 15%, and the built-in tape is 300 mm long. The tape hydrocyclone has the best separation efficiency. Compared with the basic hydrocyclone, the built-in twisted tape hydrocyclone with a length of 300 mm increases the separation efficiency of mud and sand by 7.49%, while the pressure drop only increases by 2.67%, showing the superiority of the built-in twisted tape structure.