Background: Machine Learning (ML) is becoming increasingly popular in healthcare, particularly for improving the timing and accuracy of diagnosis. ML can provide disease prediction by analyzing vast amounts of healthcare data, thereby, empowering patients and healthcare providers with information to make informed decisions about disease prevention. Due to the rising cost of treatment, one of the most important topics in clinical data analysis is the prediction and prevention of cardiovascular disease. It is difficult to manually calculate the chances of developing heart disease due to a myriad of contributing factors. Objective: The aim of this paper is to develop and compare various intelligent systems built with ML algorithms for predicting whether a person is likely to develop heart disease using the publicly available Cleveland Heart Disease dataset. This paper describes an alternative multilayer perceptron (MLP) training technique that utilizes a particle swarm optimization (PSO) algorithm for heart disease detection. Methods: The proposed MLP-PSO hybrid algorithm and ten different ML algorithms are used in this study to predict heart disease. Various classification metrics are used to evaluate the performance of the algorithms. Results: The proposed MLP-PSO outperforms all other algorithms, obtaining an accuracy of 84.61%. Conclusions: According to our findings, the current MLP-PSO classifier enables practitioners to diagnose heart disease earlier, more accurately, and more effectively.