Today, an important problem of the building energy performance area is carrying out multi-criteria optimizations of real building designs. To solve this problem, a new method based on a meta-model is proposed in this study. Hence, the EnergyPlus™ is used as the simulation tool for the performance simulation of the building, then a couple of the multi-criteria Modified Coot Optimization Algorithm (MCOA) dynamically combined with the artificial neural network meta-models (ANN-MM) are employed. For the sample generation applied for training and validation of ANN meta-models, an optimum way is presented by this method to minimize the whole building energy simulations needed for their training, and validate precise results of optimization. Moreover, the method is used for the thermal comfort and energy efficiency optimization of a real house to achieve the optimum balance between the heating and cooling behavior of the case building. 12 effective design variables of this case study are selected. Also, the achieved results are put in comparison with the “true” Pareto front found through an optimization method based on simulation performed for more validation. It is assumed that 1280 points are adequate in this case study to obtain precise results on the Pareto set. Thus, 75% of the required simulations’ number based on physics has been saved by this size of sample considering the 5120 applied in the method based on simulation. Consequently, the optimum Pareto set of a real multi-criteria building efficiency optimization problem is achieved by the proposed method and accurate results are achieved.