In a European context characterized by growing need for operational flexibility across the electricity sector, the combined cycle power plants are increasingly subjected to cyclic operation. These new operation profiles cause an increase of production costs and decrease of revenues, which undermines the competitiveness of the combined cycles. Power plant operators need tools to predict the effect of off-design operation and control mechanisms on the performance of the power plant. Traditional Thermodynamic or Thermoeconomic models may be unpractical for the operators, due to their complexity and the computational effort they require. This study proposes a Thermoeconomic Input–Output Analysis model for the on- and off-design performance prediction of energy systems, and applies it to La Casella Natural Gas Combined Cycle (NGCC) power plant, in Italy. It represents a stand-alone, reduced order model, where the cost structure of the plant products and the Thermoeconomic performance indicators are derived for on- and off-design conditions as functions of the load and of different control mechanisms, independently from the Thermodynamic model. The results of the application show that the Thermoeconomic Input–Output Analysis model is a suitable tool for power plant operators, able to derive the same information coming from traditional Thermoeconomic Analysis with reduced complexity and computational effort.