In this work, a comprehensive methodology for wind turbine blade design optimization is proposed. Accordingly, a numerical model based on computational fluid dynamics (CFD) has been initially coupled to a genetic algorithm (GA)-based optimization tool. Next, several optimization processes of a wind turbine blade mid-span airfoil have been carried out using the coupled tool. Finally, using the optimum airfoil and blade element momentum (BEM) theory, a wind turbine rotor has been designed and different rotor analyses at design and off-design point conditions have been carried out. Wind turbine blades operating at a 6 m/s wind speed and rated at a 5 kW power output are particularly considered. The use of aerodynamic characteristics of a blade mid-span airfoil for wind turbine blade design and optimization represents one the main features of the methodology developed here. The optimization results show that the determined optimum airfoil features better lift to drag ratios than a NACA 4412 one. From the design of the 5 kW power output wind turbine, blade lengths of 5.244 m were obtained. For the design point regarding a tip speed ratio of 6, a maximum power coefficient (Cp) of 0.4658 was computed. The aerodynamic analysis carried out at design and off-design conditions show consistent results compared to past works. The results confirm that a representative airfoil located between 25 and 90% of the blade span can be designed and optimized to obtain improved Cp and power output horizontal axis wind turbines.