Nanomedicines have been demonstrated to have passive or active tumor targeting behaviors, which are promising for cancer chemotherapy. However, most nanomedicines still suffer from a suboptimal targeting effect and drug leakage, resulting in unsatisfactory treatment outcome. Herein, a hierarchical responsive nanomedicine (HRNM) is developed for programmed delivery of chemotherapeutics. The HRNMs are prepared via the self‐assembly of cyclic Arg‐Gly‐Asp (RGD) peptide conjugated triblock copolymer, poly(2‐(hexamethyleneimino)ethyl methacrylate)‐poly(oligo‐(ethylene glycol) monomethyl ether methacrylate)‐polyreduction‐responsive camptothecin (PC7A‐POEG‐PssCPT). In blood circulation, the RGD peptides are shielded by the POEG coating; therefore, the nanosized HRNMs can achieve effective tumor accumulation through passive targeting. Once the HRNMs reach a tumor site, due to the hydrophobic‐to‐hydrophilic conversion of PC7A chains induced by the acidic tumor microenvironment, the RGD peptides will be exposed for enhanced tumor retention and cellular internalization. Moreover, in response to the glutathione inside cells, active CPT drugs will be released rapidly for chemotherapy. The in vitro and in vivo results confirm effective tumor targeting, potent antitumor effect, and reduced systemic toxicity of the HRNMs. This HRNM is promising for enhanced chemotherapeutic delivery. A hierarchical responsive nanomedicine, which can achieve programmed targeting and triggered drug release, is developed for enhanced chemotherapeutic delivery. In physiological conditions, the nanomedicine shows high stability without obvious drug leakage. Once reaching the tumor microenvironment, the activated RGD peptides can achieve enhanced cellular uptake. Then, active camptothecin moieties are rapidly released in response to the intracellular glutathione.