The present study deals with optimization of hydraulic efficiency and shaft fatigue life of a micro cross-flow hydraulic turbine. A micro cross-flow turbine (KTP-B60) with shaft fatigue failure was considered as a case study. Numerical flow simulations were performed using a 3D- two phase flow solver, and the results have shown a good agreement with experimental data. Using an analytical method, the shaft fatigue factor of safety (FOS) was extracted from numerical simulation. CFD results were utilized in the optimization process in order to improve hydraulic efficiency and shaft fatigue life simultaneously using a meta- model (Artificial Neural Network) and genetic algorithm (GA). The priority of hydraulic efficiency and shaft fatigue life was altered by defining different objective functions in the optimization process. In one of the cases comparison of initial and optimal turbine showed a hydraulic efficiency improvement of 10.14 % and relative shaft FOS improvement of 4.86 %. The proposed optimization method could be exploited as an efficient and low cost procedure for energy generation improvement in micro hydro turbines.