Nasopharyngeal carcinoma (NPC) is one of the most common head and neck malignancies and is typically treated with radiotherapy and chemotherapy. Garcinone C, a natural compound isolated from Garcinia oblongifolia Champ., is a xanthone derivative with potential cytotoxic effects on certain cancers. However, there are limited studies regarding its effects on NPC cells, and its mechanism of action in NPC remains unknown. In the present study, we found that garcinone C significantly inhibited cell viability of the human NPC cell lines CNE1, CNE2, HK1 and HONE1. This inhibition was exerted in a time‑ and dose‑dependent manner. Flow cytometry demonstrated that garcinone C arrested the cell cycle at the S phase. Moreover, with 10 µM of high‑dose garcinone C treatment, the cells exhibited necrotic morphology changes including cell swelling, rough endoplasmic reticulum degranulation, endoplasmic reticulum dilatation, mitochondrial swelling and vacuolar degeneration. In addition, we found that garcinone C stimulated the expression levels of ATR and 4E‑BP1, while efficiently inhibiting the expression levels of cyclin B1, cyclin D1, cyclin E2, cdc2, CDK7 and Stat3. Collectively, the ability of garcinone C to inhibit NPC in growth in vitro suggested that garcinone C may be a novel agent for the management of NPC.