Traditional surgical treatment is difficult to thoroughly remove esophageal squamous cell carcinomas (ESCC), and postoperative recurrence caused by residual tumor cells is a critical factor in the poor prognosis. Since surgical resection promotes the local angiogenesis at the tumor site, further exacerbating the proliferation and invasion of residual tumor cells, it is urgent to inhibit angiogenesis after surgery. Here, a functional peptide-based nanomedicine was obtained from peptide–drug conjugates, which are composed of a hydrophilic targeting motif (vascular endothelial growth factor family and their receptors (VEGFR) targeting peptide for anti-angiogenesis), and an ester-linked hydrophobic oridonin (ORI). The nanomedicine exhibits esterase-catalyzed disassembly and drug release, and significantly enhanced the anti-tumor efficacy of chemotherapeutics in a postoperative tumor recurrence model through synergistic anti-angiogenic strategies. This study provides an integrated solution for anti-angiogenesis-augmented chemotherapy and demonstrates the encouraging potential for postoperative treatment.