Hypopharyngeal carcinoma (HPC) is a subtype of head and neck squamous cell carcinoma, and prognosis has improved significantly over the past three decades. Induction docetaxel/cisplatin/5 fluorouracil (TPF) chemotherapy is regarded as the standard of treatment for locoregionally advanced HPC. However, patients who do not respond to cisplatin suffer, rather than benefit, from chemotherapy treatment. The goal of this study was to identify molecules involved in TPF resistance and to clarify their molecular mechanisms. Using the FaDu cell line as the cell model, the TPF IC50 was identified, and c-Jun, IL6, Camk2a, c-fos knockdown using siRNAs resulted in a significant declined TPF IC50. Retrospective analysis of the expression status of c-Jun, IL6, Camk2a, and c-fos by immunohistochemistry staining in sectioned HPC tissues from TPF-sensitive and TPF-insensitive patients shows that Camk2a and c-Jun were associated with the clinical pathogenesic features in HPC. The in vitro experiments also indicate that both Camk2a and c-Jun were responsive to TPF treatment. This study identified Camk2a and c-Jun as candidate genes that confer induction TPF resistance, which would help in the discovery of potential therapeutic markers and in developing a personalized and precise treatment approach for HPC patients.