The need for high performances is pushing the complexity of mechanical design at very high levels, especially for turbomachinery components. In this field, structural topology optimization methods together with additive manufacturing techniques for high-resistant alloys are considered very promising tools, but their potentialities have not been deeply investigated yet for critical rotating components like new-generation turbine blades. In this context, this research work proposes a methodology for the design, the optimization, and the additive manufacturing of extremely stressed turbomachinery components like turbine blade rows. The presented procedure pays particular attention to important aspects as fluid–structure interactions (forced response and flutter phenomena) and fatigue behavior of materials, going beyond the standard structural optimization approaches. The new design strategy enables a substantial reduction of the component mass, limiting the maximum stress and improving the vibrational behavior of the system in terms of eigenfrequencies, modal shapes, and fatigue life. Furthermore, the numerical procedure shows robustness and efficiency, making the proposed methodology an appropriate tool for rapid design and prototyping and for reducing the design costs and the typical time to market of this type of mechanical elements. The procedure has been applied to a low-pressure turbine rotor to improve the aeromechanical characteristics while keeping the aerodynamic performance. From the original geometry, mode-shapes, forcing functions (due to rotor/stator interactions), and aerodynamic damping have been numerically evaluated and used as input data for the subsequent topological optimization. Finally, the optimized geometry has been numerically and experimentally verified to confirm the improved aeromechanical design. After the structural topology optimization, the final geometries provided by the procedure have been properly rendered to make them suitable for additive manufacturing. Some prototypes of the new optimized turbine blade have been manufactured from aluminum alloy to be tested mechanically and in terms of fatigue.