Abstract Motivation The origins of replication sites (ORIs) are precise regions inside the DNA sequence where the replication process begins. These locations are critical for preserving the genome’s integrity during cell division and guaranteeing the faithful transfer of genetic data from generation to generation. The advent of experimental techniques has aided in the discovery of ORIs in many species. Experimentation, on the other hand, is often more time-consuming and pricey than computational approaches, and it necessitates specific equipment and knowledge. Recently, ORI sites have been predicted using computational techniques like motif-based searches and artificial intelligence algorithms based on sequence characteristics and chromatin states. Results In this article, we developed ORI-Explorer, a unique artificial intelligence-based technique that combines multiple feature engineering techniques to train CatBoost Classifier for recognizing ORIs from four distinct eukaryotic species. ORI-Explorer was created by utilizing a unique combination of three traditional feature-encoding techniques and a feature set obtained from a deep-learning neural network model. The ORI-Explorer has significantly outperformed current predictors on the testing dataset. Furthermore, by employing the sophisticated SHapley Additive exPlanation method, we give crucial insights that aid in comprehending model success, highlighting the most relevant features vital for forecasting cell-specific ORIs. ORI-Explorer is also intended to aid community-wide attempts in discovering potential ORIs and developing innovative verifiable biological hypotheses. Availability and implementation The used datasets along with the source code are made available through https://github.com/Z-Abbas/ORI-Explorer and https://zenodo.org/record/8358679.