Abstract In low-temperature waste heat recovery for organic Rankine cycle (ORC) power generation, the radial-inflow turbine (RIT) plays a crucial role. This study focuses on the preliminary design, three-dimensional simulations, and optimization of a 200 kW RIT for R245fa working fluid. The turbine’s preliminary design relies on selected empirical coefficients, leading to performance uncertainty. The performance of the turbine obtained from the initial design was evaluated using computer simulations, indicating that achieving outstanding isentropic efficiency and power targets solely relying on the design of empirical coefficients can sometimes be challenging. Design of Experiments (DOE) on five variables was performed using the Isight platform, highlighting rotor inlet blade height as crucial for turbine performance. The optimized RIT showed a 10.5% efficiency increase and 45.6 kW power gain. Entropy production analysis confirmed substantial improvement. Systematic theoretical calculations followed by DOE optimization effectively enhance turbine efficiency, providing valuable and innovative insights for satisfactory design solutions.