Deep Neural Networks have achieved many successes when applying to visual, text, and speech information in various domains. The crucial reasons behind these successes are the multi-layer architecture and the in-model feature transformation of deep learning models. These design principles have inspired other sub-fields of machine learning including ensemble learning. In recent years, there are some deep homogenous ensemble models introduced with a large number of classifiers in each layer. These models, thus, require a costly computational classification. Moreover, the existing deep ensemble models use all classifiers including unnecessary ones which can reduce the predictive accuracy of the ensemble. In this study, we propose a multi-layer ensemble learning framework called MUlti-Layer heterogeneous Ensemble System (MULES) to solve the classification problem. The proposed system works with a small number of heterogeneous classifiers to obtain ensemble diversity, therefore being efficiency in resource usage. We also propose an Evolutionary Algorithm-based selection method to select the subset of suitable classifiers and features at each layer to enhance the predictive performance of MULES. The selection method uses NSGA-II algorithm to optimize two objectives concerning classification accuracy and ensemble diversity. Experiments on 33 datasets confirm that MULES is better than a number of well-known benchmark algorithms.