Accurately predicting students’ future performance based on their ongoing academic records is crucial for effectively carrying out necessary pedagogical interventions to ensure students’ on-time and satisfactory graduation. Although there is a rich literature on predicting student performance when solving problems or studying for courses using data-driven approaches, predicting student performance in completing degrees (e.g., college programs) is much less studied and faces new challenges: (1) Students differ tremendously in terms of backgrounds and selected courses; (2) courses are not equally informative for making accurate predictions; and (3) students’ evolving progress needs to be incorporated into the prediction. In this paper, we develop a novel machine learning method for predicting student performance in degree programs that is able to address these key challenges. The proposed method has two major features. First, a bilayered structure comprising multiple base predictors and a cascade of ensemble predictors is developed for making predictions based on students’ evolving performance states. Second, a data-driven approach based on latent factor models and probabilistic matrix factorization is proposed to discover course relevance, which is important for constructing efficient base predictors. Through extensive simulations on an undergraduate student dataset collected over three years at University of California, Los Angeles, we show that the proposed method achieves superior performance to benchmark approaches.