<p>As the incidence of heart failure continues to rise globally, the demand for interventional blood pumps for heart failure treatment has increased. However, the use of these pumps may lead to infection issues. Given the limited research on blood pump infections, methods for evaluating the risk of infection are crucial. In this study, first, an infection risk assessment model for blood pumps was constructed to quantify the relationships among the loss rate of leukocytes, shear strain rate, and temperature. A computational fluid dynamics (CFD) simulation model was subsequently developed to perform fluid–thermal coupling simulations of the internal flow field, temperature field, and index of infection of the blood pump. Furthermore, the impeller design was optimized via an orthogonal experimental design and regression analysis to reduce the risk of infection. Finally, in vitro experiments were conducted to validate the accuracy of the simulation results. Numerical simulations demonstrated that the impeller design significantly influenced the risk of infection. The optimized impeller design (with a larger proximal fillet radius and a smaller blood outlet axial length) reduced the risk of infection. The trends observed in the in vitro experimental results were consistent with the simulation values. The impeller optimization design method proposed in this study effectively reduces the risk of infection in interventional blood pumps, providing a theoretical basis and practical guidance for the design and risk assessment of interventional blood pumps.</p>