Cell-penetrating peptides (CPPs) are considered as promising drug carriers by virtue of their potent cell-penetrating capacity. However, lack of targetability still represents a bottleneck for their systemic administration. Here, we synthesized a lysine-rich CPP named KRP and developed a tumor-targeted drug delivery system (DDS) by linking KRP and doxorubicin (DOX) with stable covalent bonds (thioether bond and amide bond). Through in vitro and in vivo tests, we confirmed that the multiple physicochemical properties of KRP endow KRP-DOX with multiple synergistic functions, including good biocompatibility and biodistribution, selective accumulation in tumor tissues, inclination to remain in tumor tissues and be internalized by tumor cells; stable covalent bonds prevent free DOX release from KRP-DOX in blood stream, shield normal tissues from the toxic effect of DOX, and lead to the majority of DOX delivery into tumor cells by KRP; lysosome escape of KRP-DOX ensures its tumor-killing effect. In addition, the simple chemical composition and modification reduce the risk of immunogenicity and metabolite toxicity. Our study provides a simple, safe, and efficient platform for tumor-targeted DDS.