A novel hybrid perfusion manipulator (HPM) with five degrees of freedom (DOFs) is introduced by combining the 5PUS-PRPU (P, R, U and S represent prismatic, revolute, universal and spherical joint, respectively) parallel mechanism with the 5PRR reconfigurable base to enhance the perfusion efficiency of the large-scale spherical honeycomb thermal protection layer. This study mainly presents the dimensional synthesis of the proposed HPM. First, the inverse kinematics, including the analytic expression of the rotation angles of the U joint in the PUS limb, is obtained, and mobility analysis is conducted based on screw theory. The Jacobian matrix of 5PUS-PRPU is also determined with screw theory and used for the establishment of the objective function. Second, a global and comprehensive objective function (GCOF) is proposed to represent the Jacobian matrix’s condition number. With the genetic algorithm, dimensional synthesis is conducted by minimizing GCOF subject to the given variable constraints. The values of the designed variables corresponding to different configurations of the reconfigurable base are then obtained. Lastly, the optimal structure parameters of the proposed 5-DOF HPM are determined. Results show that the HPM with the optimized parameters has an enlarged orientation workspace, and the maximum angle of the reconfigurable base is decreased, which is conducive to improving the overall stiffness of HPM.