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Head and neck squamous cell carcinomas (HNSCCs) remain a significant clinical challenge due to treatment resistance and therapy-associated toxicity. Here, we evaluate the therapeutic potential and mechanism of action of AOH1996, a first-in-class small molecule that targets a cancer-associated isoform of proliferating cell nuclear antigen (caPCNA). Across HPV-positive and HPV-negative HNSCC models, AOH1996 induces robust cytotoxicity associated with mitotic arrest, multipolar mitosis, failed cytokinesis, cell-cell fusion, and DNA damage. Live-cell imaging reveals widespread mitotic catastrophe with limited successful mitotic progression. Notably, AOH1996 sensitivity correlates with c-Myc abundance, suggesting a potential biomarker of response. In vivo, AOH1996 suppresses tumor growth with minimal toxicity in xenograft models. Together, these findings establish AOH1996 as a promising therapeutic candidate that disrupts mitotic fidelity and induces cancer-selective cytotoxicity in HNSCC.