The hypercube optimization search (HOS) approach is a new efficient and robust metaheuristic algorithm that simulates the dove’s movement in quest of new food sites in nature, utilizing hypercubes to depict the search zones. In medical informatics, the classification of medical data is one of the most challenging tasks because of the uncertainty and nature of healthcare data. This paper proposes the use of the HOS algorithm for training multilayer perceptrons (MLP), one of the most extensively used neural networks (NNs), to enhance its efficacy as a decision support tool for medical data classification. The proposed HOS-MLP model is tested on four significant medical datasets: orthopedic patients, diabetes, coronary heart disease, and breast cancer, to assess HOS’s success in training MLP. For verification, the results are compared with eleven different classifiers and eight well-regarded MLP trainer metaheuristic algorithms: particle swarm optimization (PSO), biogeography-based optimizer (BBO), the firefly algorithm (FFA), artificial bee colony (ABC), genetic algorithm (GA), bat algorithm (BAT), monarch butterfly optimizer (MBO), and the flower pollination algorithm (FPA). The experimental results demonstrate that the MLP trained by HOS outperforms the other comparative models regarding mean square error (MSE), classification accuracy, and convergence rate. The findings also reveal that the HOS help the MLP to produce more accurate results than other classification algorithms for the prediction of diseases.