Background: Liquid biopsy, especially circulating tumor DNA (ctDNA), has been reported to provide information on tumor genetic features and possible disseminated disease in many kinds of solid tumors. In this pilot study, we investigated the utilization of ctDNA for monitoring treatment response and progression of the disease in patients with head and neck cancers (HNC) by next-generation sequencing (NGS). Methods: We sequenced ctDNA from 24 plasma samples collected at different time points from 19 HNC patients undergoing surgery or chemotherapy using a targeted gene panel composed of 61 actionable genes recurrently mutated in human malignancies in Tongren Hospital from November 2016 to February 2018. Also, the presence or absence of the residual ctDNA after chemotherapy in 9 patients was associated with the treatment efficacy evaluated by computed tomography (CT). Results: We found that TP53 (2/6) and PIK3CA (2/6) are the most commonly recurring mutated genes. Out of 7 patients with matched tissue and pre-treatment blood samples, we confirmed concordance of ctDNA mutation in 5 patients. In 4 post-surgery patients with undetectable ctDNA mutation, ctDNA did not reoccur during the follow-up period of over 20 months. Conclusions: These results suggested that NGS detection of ctDNA may contribute to minimal residual disease (MRD) detection and chemotherapy efficacy prediction in HNC.