Background: Esophageal cancer has a high incidence and one of the highest mortality rates worldwide. There are few studies on the effects of sevoflurane on postoperative metastasis and recurrence of esophageal cancer. This study aimed to investigate the effect of sevoflurane on the progression of esophageal cancer and the underlying mechanism of the sensitivity to cisplatin. Methods: We used the esophageal squamous cell carcinoma (ESCC) line EC109 and esophageal adenocarcinoma (EADC) line SKGT-4. Cell proliferation and stemness potential were determined by MTT assay and sphere-forming assays, respectively. The protein expression of (sex determining region Y)box 2 (SOX2) and octamer-binding transcription factor 4 (OCT4) was determined by western blot. Cell migration and invasion ability were separately determined by scratch assay and transwell assays, respectively. The distribution of cell cycle and apoptosis were detected by flow cytometry, and the levels of lactate dehydrogenase (LDH) were measured by the enzyme-linked immunosorbent assay (ELISA). Results: In the SKGT-4 cells, exposure to sevoflurane inhibited proliferation, increased the migration and invasion potential, increased the number of cells in S phase, promoted self-renewal ability, and up-regulated the expression of SOX2 and OCT4 compared with control cells. Compared with the cisplatin treated group, treatment with sevoflurane plus cisplatin reduced the level of LDH and inhibited apoptosis in the SKGT-4 cells. However, sevoflurane did not affect EC109 cells. Conclusions: Long-term exposure to sevoflurane inhibited the proliferation, increased migration and invasion capacity, and decreased the sensitivity to cisplatin in EADC by promoting stemness. However, sevoflurane had no effect on the behavior of ESCC.