As an indispensable equipment in thermal power plants, the high-power coolant pump is necessary for high hydraulic performance with good structural safety for transferring of heat produced by fuels. However, the design of blade thickness for coolant pump especially at the off-design condition is still empirical and arbitrary. In the present work, the hydraulic performance, internal flow pattern, and structural response arising from the variations of blade thickness in coolant pump have been investigated using computational fluid dynamics and fluid–structure interaction methods. The numerical results have been verified by experimental performance and found to be good. To improve the accuracy of head calculation at the overload condition, a modified equation is proposed with the help of multi-island genetic algorithm and the average deviation is reduced from 58.50 to 1.59%. With the blade thickening process, the hydraulic performance is gradually deteriorated especially at the overload condition, and the flow behavior is changed with the proportion of high velocity near the pressure surface enlarging, the proportion of low velocity near the suction surface decreasing, and the pressure fluctuation intensity rising. Besides, increasing the blade thickness beyond 23.0 mm, the stress reduction is not effective. However, it helps to increase the natural frequency for suppressing the resonance. Finally, considering the optimal hydraulic and structural performances, the blade thickness is optimized to 23.0 mm.