The widespread impact of thyroid disease and its diagnosis is a challenging task for healthcare experts. The conventional technique for predicting such a vital disease is complex and time-consuming. A data-driven approach may offer predictive solutions, but it relies on all relevant attributes, which are computationally expensive. Hence, we propose a novel machine learning (ML) based disease prediction system that could potentially predict it by considering three crucial steps. First, to reduce the dimension of the dataset, three feature selection techniques were employed, including Feature Importance (FIS), Information Gain Selections (IGS), and Least Absolute Shrinkage and Selection Operator (LAS). Moreover, recommended medical references were considered while developing a feature set having the identical attributes as High-Risk Factors (HRF). Second, the models, including the Three Stage Hybrid Classifier (3SHC) and the Three Stage Hybrid Artificial Neural Network (3SHANN), are used as classifiers on the training data set. Third, a Local Interpretable Model-agnostic Explanations (LIME) to the 3SHC with the HRF samples was applied to individually explain the predictions. Then, the overall behaviors of both gender and age categories were explored with the help of a Partial Dependence Plot (PDP). Finally, the proposed system is validated with extensive experiments where the 3SHC achieves an accuracy (ACC) of 99.29%, which can play a crucial role in preventing thyroid disease and alleviating stress in the healthcare sector.