This study presents a numerical approach to the design and optimization of centrifugal impellers used in the pumps of active thermal control systems of spacecraft. Although launch costs have shrunk in the last decade, the performance requirements, such as efficiency and reliability, have increased, as such systems are required to work up to 15 years, depending on the mission. To that effect, our paper deals with the first step in this pump design, namely the hydraulic optimization of the impeller. Constructively, this type of impeller allows for certain balancing systems and labyrinth seals to be applied in a more effective way, as well as allowing for additive manufacturing methods to be used—however, details regarding these aspects are beyond the scope of the current paper. By combining empirical formulas, computational fluid dynamics (CFD) analysis, and artificial neural networks (ANNs), the research focuses on achieving high efficiency and fast manufacturing. A series of geometries have been sized and validated using steady-state RANS (Reynolds Averaged Navier-Stokes) simulations, leading to the identification of the most efficient configuration. Subsequent optimization using an ANN resulted in a refined impeller design with notable improvements in hydraulic performance: a 3.55% increase in efficiency and a 7.9% increase in head. Key parameters influencing impeller performance, including blade number, incidence, and backsweep angles, are identified. This approach offers a comprehensive method to address the evolving requirements of space missions and contributes to the advancement of centrifugal pump technology in the space domain.