Tomato yellow leaf curl virus (TYLCV) dispersed across different countries, specifically to subtropical regions, associated with more severe symptoms. Since it was first isolated in 1931, TYLCV has been a menace to tomato industrial production worldwide over the past century. Three groups were newly isolated from TYLCV-resistant tomatoes in 2022; however, their functions are unknown. The development of machine learning (ML)-based models based on characterized sequences and evaluating blind predictions is 1 of the major challenges in interdisciplinary research. The purpose of this study was to develop an integrated computational framework for the accurate identification of symptoms (mild or severe) based on TYLCV sequences (isolated in Korea). For the development of the framework, we first extracted 11 different feature encodings and hybrid features from the training data and then explored 8 different classifiers and developed their respective prediction models by using randomized 10-fold cross-validation. Subsequently, we carried out a systematic evaluation of these 96 developed models and selected the top 90 models, whose predicted class labels were combined and considered as reduced features. On the basis of these features, a multilayer perceptron was applied and developed the final prediction model (IML-TYLCVs). We conducted blind prediction on 3 groups using IML-TYLCVs, and the results indicated that 2 groups were severe and 1 was mild. Furthermore, we confirmed the prediction with virus-challenging experiments of tomato plant phenotypes using infectious clones from the 3 groups. Plant virologists and plant breeding professionals can access the user-friendly online IML-TYLCVs web server at https://balalab-skku.org/IML-TYLCVs, IML-TYLCVs, which can guide them in developing new protection strategies for newly emerging viruses.