Pro-oxidant therapy using chemical agents that can encourage oxidative stress in cancer cells has been attempted for cancer-specific therapy. Piperlongumine (PL) is known as an innovative pro-oxidant agent because it shows cancer-specific cytotoxicity via elevation of intracellular ROS in cancer cells through inhibition of PI3K/Akt/mTOR pathway. However, therapeutic utility of PL is hampered by its poor water-solubility, which requires appropriate drug carriers for PL delivery. In this study, poly(ethylene glycol)-poly(histidine) [PEG-poly(His)] copolymer was synthesized and formulated as micelles with PL. It was demonstrated that the PL-loaded PEG-poly(His) micelles [PL-PEG-poly(His)] induce pH-sensitive drug release due to protonation of the imidazole groups in the poly(His) under acidic conditions. Plain PEG-poly(His) micelles without PL were innocuous, indicating their high biocompatibility. Interestingly, PL-PEG-poly(His) micelles exhibited remarkable cytotoxicity in cancer cells over normal cells. PL-PEG-poly(His) micelles were further modified with folic acid (FA) to enhance their cancer-specificity. As compared to FA-free micelles, FA-PL-PEG-poly(His) micelles manifested more increased cellular uptake and anticancer efficacy against folate receptor-positive cancer cells. This study demonstrates that PL-PEG-poly(His) micelles have great potential as effective PL delivery and cancer-targeted pro-oxidant therapy.