Combination therapy is a promising clinical treatment strategy for cancer and other complex diseases. Multiple drugs can target multiple proteins and pathways, greatly improving the therapeutic effect and slowing down drug resistance. To narrow the search space of synergistic drug combinations, many prediction models have been developed. However, drug combination datasets always have the characteristics of class imbalance. Synergistic drug combinations receive the most attention in clinical application but are in small numbers. To predict synergistic drug combinations in different cancer cell lines, in this study, we propose a genetic algorithm-based ensemble learning framework, GA-DRUG, to address the problems of class imbalance and high dimensionality of input data. The cell-line-specific gene expression profiles under drug perturbations are used to train GA-DRUG, which contains imbalanced data processing and the search of global optimal solutions. Compared to 11 state-of-the-art algorithms, GA-DRUG achieves the best performance and significantly improves the prediction performance in the minority class (Synergy). The ensemble framework can effectively correct the classification results of a single classifier. In addition, the cellular proliferation experiment performed on several previously unexplored drug combinations further confirms the predictive ability of GA-DRUG.