Combining one-dimensional parameter optimization and three-dimensional modeling optimization, a 30 kW radial inflow turbine for ocean thermal energy conversion was designed. In this paper, the effects of blade tip clearance, blade number, twist angle, and wheel–diameter ratio on the radial inflow turbine were analyzed. The results show that the model prediction method based on 3D numerical simulation data can effectively complete secondary optimization of the radial turbine rotor. The prediction model can be used to directly obtain the optimal modeling parameter of the rotor. The tip clearance, blade number, twist angle, wheel–diameter ratio, and shaft efficiency were found to be 0.273 mm, 16, 43.378°, 0.241, and 88.467%, respectively. The optimized shaft efficiency of the turbine was found to be 2.239% higher than the one-dimensional design result, which is of great significance in reducing the system’s power generation costs and promoting the application of this approach in engineering power generation using ocean thermal energy.