A variety of algorithms have been developed for catalytic residue prediction based on either feature- or template-based methodology. However, no studies have systematically compared these two strategies and further considered whether their combination could improve the prediction performance. Herein, we developed an integrative algorithm named CRHunter by simultaneously using the complementarity between feature- and template-based methodologies and that between structural and sequence information. Several novel structural features were generated by the Delaunay triangulation and Laplacian transformation of enzyme structures. Combining these features with traditional descriptors, we invented two support vector machine feature predictors based on both structural and sequence information. Furthermore, we established two template predictors using structure and profile alignments. Evaluated on datasets with different levels of homology, our feature predictors achieve relatively stable performance, whereas our template predictors yield poor results when the homological relationships become weak. Nevertheless, the hybrid algorithm CRHunter consistently achieves optimal performance among all our predictors. We also illustrate that our methodology can be applied to the predicted structures of enzymes. Compared with state-of-the-art methods, CRHunter yields comparable or better performance on various datasets. Finally, the application of this algorithm to structural genomics targets sheds light on solved protein structures with unknown functions.