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In this study, the objective was to develop a new and highly-accurate artificial intelligence model for slope failure prediction in open-pit mines. For this purpose, the M5Rules algorithm was combined with a genetic algorithm (GA) in a novel hybrid technique, named M5Rules–GA model, for slope stability estimation and analysis and 450-slope observations in an open-pit mine in Vietnam were modeled using the Geo-Studio software based on essential parameters. The factor of safety was used as the model outcome. Artificial neural networks (ANN), support vector regression (SVR), and previously introduced models (such as FFA-SVR, ANN-PSO, ANN-ICA, ANN-GA, and ANN-ABC) were also developed for evaluating the proposed M5Rules–GA model. The evaluation of the model performance involved applying and computing the determination coefficient, variance account for, and root mean square error, as well as a general ranking and color scale. The results confirmed that the proposed M5Rules–GA model is a robust tool for analyzing slope stability. The other investigated models yielded less robust performance under the evaluation metrics.