In electric vehicle thermal management systems, direct measurement of the internal motor temperature is difficult. Therefore, the coolant pressure drop is an important indicator for estimating the motor thermal state. However, manufacturing and operating uncertainties in water-cooled interior permanent magnet synchronous motors (IPMSMs) can cause variability in cooling performance and pressure drop, requiring a reliability-based design approach. In this study, reliability-based design optimization (RBDO) is performed by considering manufacturing tolerances in the cooling channels and uncertainty in the inlet coolant flow rate. Based on coupled electromagnetic–thermal–fluid analysis and Kriging surrogate models, RBDO is applied to minimize the maximum temperature while satisfying the allowable pressure-drop limit at a target reliability level. The proposed RBDO improves the probability of satisfying the pressure-drop constraint from 54.1% in the baseline design to 99.9%, while increasing the mean maximum temperature by only 0.17 K. These results indicate that RBDO can improve the reliability of the pressure-drop constraint in IPMSM water-cooling systems under practical manufacturing and operating uncertainties, with only a limited change in thermal performance.