The tetra-peptide AVPI, derived from the Smac/DIABLO N-terminal epitope, is able to trigger caspase activation and apoptotic process. However, its clinical value is greatly hampered by the nature of membrane-impermeability. Herein, the cell-penetrating chimeric apoptotic peptide of AVPIR8 is synthesized, of which the apoptosis-induced AVPI is strategically blended with the cell-penetrating sequence of octaarginine (R8). The dual-functionalized AVPIR8 is not only potent in inducing apoptosis in tumor cells due to the cell penetration ability, but also is able to work as gene carrier for transfering the tumor suppressor p53 DNA into cells, thus constructing a co-delivery drug system (AVPIR8/p53). Such system efficiently promotes apoptosis in cancer cells while sparing normal cells, and its antitumor activity is further significantly enhanced in combination with doxorubicin as cocktail therapy. More importantly, the anticancer efficacy of the cocktail is demonstrated to be able to arrest tumor growth in two animal tumor models (melanoma and cervical cancers), respectively. The chemotherapeutic dose in the AVPIR8/p53-based cocktail is significantly reduced by 80%, compared to the monotherapy of doxorubicin. The present results show the promise of the co-delivered AVPIR8/p53 as adjuvant therapy for boosting the conventional chemotherapeutics, with a unique benefit of enhanced productive treatment outcomes yet greatly reduced adverse toxicity.