Sevoflurane (SEVO) is widely applied as an anesthetic. More recently, its antitumor capacity has been reported. However, potent mechanisms are still incompletely ascertained. In our current study, we attempted to elucidate a potent mechanism associated with microRNA (miR)‐29a/DNA methyltransferase 3 alpha (Dnmt3a) in hepatocellular carcinoma (HCC) cells. After transfection and stimulation with SEVO, biological activities of Huh7 and HepG2 cells were evaluated using the cell counting kit‐8, Annexin V‐fluorescein isothiocyanate apoptosis detection kit, 24‐well cell migration assay kit, and tumor invasion 24‐well plates. miR‐29a and protein expression were quantified with quantitative reverse transcription polymerase chain reaction and Western blot assay, respectively. A Dual‐Luciferase Reporter Assay System was used to verify whether miR‐29a targets Dnmt3a. We found that SEVO alleviated cell viability, aggrandized apoptosis, and impeded migration and invasion of the Huh7 and HepG2 cells. Besides, SEVO enhanced phosphatase and tensin homolog (PTEN) expression, and phosphorylated expression of phosphatidylinositol 3 kinase (PI3K), and protein kinase B (AKT) was eliminated by SEVO. Of note, SEVO restored miR‐29a which was downregulated in HCC tissues and cells. miR‐29a inhibitor abolished the positive effects of SEVO on the biological processes. Dual‐Luciferase Reporter assay showed miR‐29a repressed Dnmt3a expression via targeting its 3′‐untranslated region. Further, exogenous expression of Dnmt3a partially repressed PTEN and enhanced phosphorylated expression of PI3K and AKT which were originally elevated or diminished by SEVO. In conclusion, SEVO restored the expression of miR‐29a, which posttranscriptionally downregulated Dnmt3a, and then exhibited an antitumor property in HCC cells.