Multidrug resistance (MDR) is a significant challenge in cancer treatment, with limited effective strategies available. Neuropilin-1 (NRP1) is emerging as a potential therapeutic target for overcoming drug resistance, but its role in MDR and the identification of potential inhibitors require further exploration. In this study, we investigated the role of NRP1 in MDR and identifies potential inhibitors targeting NRP1. Elevated NRP1 expression was observed in oxaliplatin (OXP)-resistant HCT116 (HCT116/L) and cisplatin (DDP)-resistant A549 cells (A549/DDP). Virtual screening and biological assays identified pitavastatin (Ptv) as a potent NRP1 inhibitor that restored chemosensitivity in resistant cells both in vitro and in vivo. Mechanistic studies revealed that Ptv directly binds to NRP1, promotes degradation of Zinc finger X-chromosomal protein (ZFX), and disrupts the NRP1-ZFX axis to reverse MDR. This study provides promising prospects for targeting the NRP1-ZFX axis as a therapeutic strategy for MDR and highlights the potential clinical application of Ptv in diseases involving NRP1.