Sevoflurane, an inhalational anesthetic, is extensively used during oral cancer surgery. However, the effect of sevoflurane on head and neck squamous cell carcinoma (HNSCC) remains unclear. The objective of the present study was to investigate the effects of sevoflurane on the proliferation, apoptosis and invasion in HNSCC cell lines and the underlying molecular mechanism. The Cell Counting Kit-8 assay was used to evaluate cell proliferation. Apoptosis was analyzed by flow cytometry. Cell invasion was evaluated using the Transwell invasion assay. The expression levels of Akt, p-Akt (Ser473), hypoxia‑inducible factor-1α (HIF-1α), Fas and Bcl-2 were measured by western blotting. Significant inhibition of cell proliferation and induction of apoptosis were observed in FaDu and CAL-27 cells following sevoflurane treatment. The expression of Akt, p-Akt (Ser473) and Bcl-2 was supressed, while that of Fas was significantly increased, which was partly associated with the activation of the HIF-1α pathway. In addition, the results revealed a statistically significant inhibition of cell invasion in the FaDu cell line following exposure to 2 and 4% sevoflurane for 2, 4, 6 and 8 h. Therefore, the present study demonstrated that sevoflurane decreased the malignant behavior of HNSCC cell lines in vitro, which was associated with activation of the HIF-1α pathway.