One of the major challenges in cancer therapy lies in the limited targeting specificity exhibited by existing anti-cancer drugs. Tumor-homing peptides (THPs) have emerged as a promising solution to this issue, due to their capability to specifically bind to and accumulate in tumor tissues while minimally impacting healthy tissues. THPs are short oligopeptides that offer a superior biological safety profile, with minimal antigenicity, and faster incorporation rates into target cells/tissues. However, identifying THPs experimentally, using methods such as phage display or in vivo screening, is a complex, time-consuming task, hence the need for computational methods. In this study, we proposed StackTHPred, a novel machine learning-based framework that predicts THPs using optimal features and a stacking architecture. With an effective feature selection algorithm and three tree-based machine learning algorithms, StackTHPred has demonstrated advanced performance, surpassing existing THP prediction methods. It achieved an accuracy of 0.915 and a 0.831 Matthews Correlation Coefficient (MCC) score on the main dataset, and an accuracy of 0.883 and a 0.767 MCC score on the small dataset. StackTHPred also offers favorable interpretability, enabling researchers to better understand the intrinsic characteristics of THPs. Overall, StackTHPred is beneficial for both the exploration and identification of THPs and facilitates the development of innovative cancer therapies.