The high rotational speed of the axial flow blood pump and flow separation of the centrifugal blood pump are the leading causes of blood damage in the blood pump. Nevertheless, the mixed flow blood pump can effectively alleviate the high rotational speed and the flow separation. Based on this, the three-dimensional flow simulation of a closed impeller mixed flow blood pump was carried out by the computational fluid dynamics method. The blood pump performance with different blade numbers and thicknesses was investigated. The blood pump flow characteristics and pressure distribution were analyzed. Based on the hemolysis power function model, the Lagrangian particle tracking method was used to predict the blood pump hemolysis performance. The structural parameters with excellent hydraulic performance and hemolysis performance were obtained. The results show that the lift is closer to the expected design target when the number of the blades is 5, and the thickness is 0.8 mm, which ensures the pressure demand of the blood pump. The hemolytic index is reduced by 14.65%, and the thrombosis is effectively reduced. There is no backflow or flow fixed vortex zone due to uniform and stable internal flow. The cavitation intensity is effectively alleviated due to the reduction of low-pressure area at the blade entrance. The research results may provide a basis for the structural improvement and performance evaluation of the closed impeller mixed flow blood pump.