Drug chemoresistance remains a major reason of treatment failure in cancer patients.In head and neck squamous cell carcinoma (HNSCC), the seventh most common can-cer worldwide, cisplatin chemotherapy remains the gold standard for advanced tum-ors but often faces loss of responsiveness and the drawback of relapse. We previouslyshowed that the metabolic and angiogenic factor angiopoietin-like 4 (ANGPTL4) is amolecular biomarker of oral dysplasia and HNSCC. We also found that through inter-action with Neuropilin 1 (NRP1), ANGPTL4 activates proliferative and migratorypathways that contribute to HNSCC development. Using HNSCC xenografts, patienttumor-derived organoids, tumor spheroids, and HNSCC cell lines, CAL27, HN13,and HN4, here we provide evidence of the role of ANGPTL4 in the development ofplatinum- based chemoresistance in HNSCC through the promotion of DNA damageresponse (DDR) and homologous recombination (HR). ANGPTL4 enhanced thesemechanisms by promoting phosphorylation of RAD51 recombinase in Tyr315/54 throughan NRP1/ABL1-dependent mechanism. Pharmacologic inhibition of NRP1 or ABL1reversed ANGPTL4-mediated DDR and HR, and increased HNSCC cell death incombination with cisplatin, in vitro and in vivo. Our results reveal a role for ANGPTL4in RAD51- dependent DNA repair and suggest that ANGPTL4/NRP1/ABL1/RAD51may serve as an alternative therapeutic target for HNSCC.