● Cisplatin resistant cells and CSCs showed high SDCBP levels and formed slow-growing but highly aggressive tumors in vivo● SDCBP inhibition promoted cisplatin sensitization in HNSCC cell lines with high resistance to cisplatin, reduced tumorsphere formation, EMT traits, and CSCs fraction identified as SP● p-Src was identified as a major downstream target in SDCBP-mediated CSC properties and cisplatin resistance in HNSCC● SDCBP protein expression in HNSCC was associated with advanced tumor stage, shorter disease-free survival and overall survival. The gene discussed is SDCBP; the disease is head and neck squamous cell carcinoma.