Abstract Introduction: The Coronavirus has spread across the globe and infected millions of people, having devastating effect on the global public health and economies. A fast diagnostic system should be implemented to mitigate the impact of the virus and save lives. In this study, we propose a decision tree-based ensemble model using two mixtures of discriminative experts (MoE) to classify COVID-19 and non-COVID-19 lung infections on chest X-ray images. The Epistocracy algorithm, a hyper-heuristic evolutionary method, is employed to optimize the neural networks used in this work. Using this approach can help detect COVID-19 cases and accelerate treatment of those who need it the most. Data: we collected 2,500 chest X-ray images from Henry Ford Health System consisting of 1,250 Covid images and 1,250 non-Covid images. The input images have been cropped and resized to 224 by 224 pixels. Out of 2,500 images, we left out 500 images containing 250 Covid and 250 non-Covid for testing. The rest, 2,000 images, were used 80% for training and 20% for validation. Methods and Results: To improve the accuracy of the proposed model, first we divided our 2,000 images into 5 different clusters using K-Means clustering algorithm with VGG16 feature extractor to help build strong discriminative expert models to be used in our proposed classifier. We trained VGG16, VGG19, InceptionV3, InceptionResNetV2, MobileNetV2, EfficientNetB7, Xception, and DenseNet201 to classify each cluster into Covid and non-Covid cases. The best result was obtained from VGG16 as a base model with a deep neural network as a head model optimized by Epistocracy algorithm. Then we built a mixture of transfer learning-based experts consisting of 5 different VGG16 models supervised by InceptionV3 as a gating network. Finally, we built a decision tree-based ensemble model to determine the classification of the data using two different MoEs with highest accuracies. As a result, for initial clusters c1, c2, c3, c4, and c5 we obtained validation accuracy of 92.50%, 86.30%, 86.51%, 85.34%, and 93.62% respectively. The first MoE had 93.75% accuracy on validation, and the second MoE had 94.25%. The final ensemble model on average obtained 94% accuracy on the testing dataset. More specifically, we got 96% accuracy on Covid images and 92% accuracy on non-Covid. Conclusion: we showed that an ensemble model consisting of two mixtures of cluster-based discriminative convolutional neural network experts can be used to detect Covid from non-Covid with high accuracy, and Epistocracy algorithm can be effectively used to optimize the hyper-parameters of the proposed models. Citation Format: Seyed Ziae Mousavi Mojab, Seyedmohammad Shams, Farshad Fotouhi, Hamid Soltanian-Zadeh. EpistoNet: An ensemble of deep convolutional neural networks using mixture of discriminative experts for detecting COVID-19 on chest X-ray images [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2021 Feb 3-5. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(6_Suppl):Abstract nr P05.