The present subject matter is directed to a system and method for optimizing wind turbine operation. For example, the present disclosure is configured to generate operating data for at least one operational parameter of the wind turbine for a predetermined time period. The system can then determine a robustness measurement of at least a portion of the operating data. In general, the robustness measurement indicates the tendency of the operating data to be affected by outliers present in the operating data. In addition, the robustness measurement is typically a function of a distribution of the operating data. The present disclosure is then configured to determine at least one optimal set point for the operational parameter as a function of the robustness measurement and a power production of the wind turbine. The wind turbine can then be operated based on the optimal set point.