The exploitation efficiency of natural gas hydrate is highly affected by sand production. In this paper, hydrocyclone purification separator was designed. A combination of single factor with computational fluid dynamics (CFD) was used to optimize the structure parameters. The performance of optimized hydrocyclone was also investigated. It shows that the sand separation efficiency increases from 90.4% to 98.7%, and the natural gas hydrate separation efficiency increases from 89.5% to 97.8%. Furthermore, the cut size of sand and natural gas hydrate are as low as 3 and 2 mu m, respectively, and separation efficiency remains above 80% under inlet parameters. It can provide some reference for the design and manufacture of the in situ purification separator for gas hydrate mixture slurry.