[Abstract] Objective: To investigate the effect and mechanism of sevoflurane on the proliferation and invasion of colon cancer SW480 cells and the growth of transplanted tumor in nude mice by regulating the phosphorylation of PI3K. Methods: Colon cancer SW480 cells were treated with sevoflurane and randomly divided into control group, 0.5% sevoflurane group, 1.0% sevoflurane group and 2.0% sevoflurane group for subsequent experiments. The proliferation ability of SW480 cells was detected by Clone formation assay, mRNA expression levels of MDM2 and survivin in cells were detected by RT-PCR, invasion ability of cells was detected by Transwell assay, and protein expression levels of MDM2, survivin, VEGF, PI3K, p-PI3K, AKT and p-AKT were detected by Western blotting. PI3K activator 740Y-P was added for verification. SW480 cell transplanted tumor model was constructed on nude mice, and the tumor mass was weighed. The positive expression rates of MDM2 and VEGF in the transplanted tumor tissues were detected by Immunohistochemistry. Results: As compared with the control group and the low-dose group, the clone formation rate of SW480 cells and the number of invaded cells in the 1.0% and 2.0% sevoflurane groups were significantly decreased (all P<0.01), the mRNA and protein levels of MDM2 in the cells were significantly increased (all P<0.01), while the mRNA and protein levels of survivin were significantly decreased (all P<0.01); and the protein levels of VEGF, p-PI3K/PI3K and p-AKT/AKT were significantly decreased (all P<0.01). 740Y-P could reverse the effect of sevoflurane on the proliferation, invasion and expression of proteins associated with the PI3K/AKT signaling pathway in SW480 cells. The mass of transplanted tumor in 2.0% sevoflurane group was significantly decreased (P<0.01), and the positive MDM2 expression rate in tumor tissues was significantly increased (P<0.01), while the positive VEGF expression rate was significantly decreased (P<0.01). Conclusion: Sevoflurane inhibits the proliferation and invasion of colon cancer SW480 cells and the growth of xenografts in nude mice possibly by inhibiting PI3K phosphorylation.