Syntenin, an intracellular scaffold protein, plays a critical role in renal cell carcinoma (RCC) progression, underscoring its potential as a therapeutic target. Herein, we report a novel, highly efficient, and stable peptide inhibitor (PDPP-3) that exhibits excellent inhibitory effects on syntenin. We have constructed a combined virtual screening scheme based on pharmacophore modeling and molecular docking to identify six potential d-amino acid-containing peptide inhibitors targeting syntenin. Among them, PDPP-3 showed the best inhibitory activity against syntenin. Binding affinity experiments and biostability experiments indicated that the interaction between PDPP-3 and syntenin displayed nanomolar-level binding affinity (K