The recent global spread of monkeypox, particularly in regions where it has not historically been prevalent, has raised significant public health concerns. Early and accurate diagnosis is critical for effective disease management and control. In response, this study proposes a novel deep learning-based framework for the automated detection of monkeypox from skin lesion images, leveraging the power of transfer learning, dimensionality reduction, and advanced machine learning techniques. We utilize the newly developed Monkeypox Skin Lesion Dataset (MSLD), which includes images of monkeypox, chickenpox, and measles, to train and evaluate our models. The proposed framework employs the Xception architecture for deep feature extraction, followed by Principal Component Analysis (PCA) for dimensionality reduction, and the Natural Gradient Boosting (NGBoost) algorithm for classification. To optimize the model's performance and generalization, we introduce the African Vultures Optimization Algorithm (AVOA) for hyperparameter tuning, ensuring efficient exploration of the parameter space. Our results demonstrate that the proposed AVOA-NGBoost model achieves state-of-the-art performance, with an accuracy of 97.53%, F1-score of 97.72% and an AUC of 97.47%. Additionally, we enhance model interpretability using Grad-CAM and LIME techniques, providing insights into the decision-making process and highlighting key features influencing classification. This framework offers a highly precise and efficient diagnostic tool, potentially aiding healthcare providers in early detection and diagnosis, particularly in resource-constrained environments.