The proto-oncogene MYC encodes a nuclear transcription factor that has an important role in a variety of cellular processes, such as cell cycle progression, proliferation, metabolism, adhesion, apoptosis, and therapeutic resistance. MYC amplification is consistently observed in aggressive forms of several solid malignancies and correlates with poor prognosis and distant metastases. While the tumorigenic effects of MYC in patients with head and neck squamous cell carcinoma (HNSCC) are well known, the molecular mechanisms by which the amplification of this gene may confer treatment resistance, especially to immune checkpoint inhibitors, remains under-investigated. Here we present a unique case of a patient with recurrent/metastatic (R/M) HNSCC who, despite initial response to nivolumab-based treatment, developed rapidly progressive metastatic disease after the acquisition of MYC amplification. We conducted comparative transcriptomic analysis of this patient’s tumor at baseline and upon progression to interrogate potential molecular processes through which MYC may confer resistance to immunotherapy and/or chemoradiation and used TCGA-HNSC dataset and an institutional cohort to further explore clinicopathologic features and key molecular networks associated with MYC amplification in HNSCC. This study highlights MYC amplification as a potential mechanism of immune checkpoint inhibitor resistance and suggest its use as a predictive biomarker and potential therapeutic target in R/M HNSCC.