BackgroundIn May 2022, the World Health Organization (WHO) European Region announced an atypical Monkeypox epidemic in response to reports of numerous cases in some member countries unrelated to those where the illness is endemic. This issue has raised concerns about the widespread nature of this disease around the world. The experience with Coronavirus Disease 2019 (COVID-19) has increased awareness about pandemics among researchers and health authorities.MethodsDeep Neural Networks (DNNs) have shown promising performance in detecting COVID-19 and predicting its outcomes. As a result, researchers have begun applying similar methods to detect Monkeypox disease. In this study, we utilize a dataset comprising skin images of three diseases: Monkeypox, Chickenpox, Measles, and Normal cases. We develop seven DNN models to identify Monkeypox from these images. Two scenarios of including two classes and four classes are implemented.ResultsThe results show that our proposed DenseNet201-based architecture has the best performance, with Accuracy = 97.63%, F1-Score = 90.51%, and Area Under Curve (AUC) = 94.27% in two-class scenario; and Accuracy = 95.18%, F1-Score = 89.61%, AUC = 92.06% for four-class scenario. Comparing our study with previous studies with similar scenarios, shows that our proposed model demonstrates superior performance, particularly in terms of the F1-Score metric. For the sake of transparency and explainability, Local Interpretable Model-Agnostic Explanations (LIME) and Gradient-weighted Class Activation Mapping (Grad-Cam) were developed to interpret the results. These techniques aim to provide insights into the decision-making process, thereby increasing the trust of clinicians.ConclusionThe DenseNet201 model outperforms the other models in terms of the confusion metrics, regardless of the scenario. One significant accomplishment of this study is the utilization of LIME and Grad-Cam to identify the affected areas and assess their significance in diagnosing diseases based on skin images. By incorporating these techniques, we enhance our understanding of the infected regions and their relevance in distinguishing Monkeypox from other similar diseases. Our proposed model can serve as a valuable auxiliary tool for diagnosing Monkeypox and distinguishing it from other related conditions.