: Head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers worldwide. Due to a lack of reliable markers, HNSCC patients are usually diagnosed at a late stage, which will lead to a worse outcome. Therefore, it is critical to improve the clinical management of cancer patients. Nowadays, the development of liquid biopsy enables a minimally invasive manner to extract molecular information from HNSCCs. Thus, this review aims to outline the clinical value of liquid biopsy in early detection, real-time monitoring, and prognostic evaluation of HNSCC. : This comprehensive review focused on the characteristics as well as clinical applications of three liquid biopsy markers (CTCs, ctDNA, and exosomes) in HNSCC. What is more, it is promising to incorporate machine learning and 3D organoid models in the liquid biopsy of HNSCC. : Liquid biopsy provides a noninvasive technique to reflect the inter and intra-lesional heterogeneity through the detection of tumor cells or materials released from the primary and secondary tumors. Recently, some evolving technologies have the potential to combine with liquid biopsy to improve clinical management of HNSCC patients.