Objective: To explore the effects of FBXO22 silencing by small interfering RNA (siRNA) on invasion and migration of colon cancer cells, and futher to investigate its related molecular mechanism. Methods: The siRNA-Ctrl and siRNA-FBXO22 fragments were transfected into SW620 and HCT116 cells, and the level of FBXO22 was detected by Western bolt. The effects of interfering FBXO22 on cell invasion and migration were analyzed by Transwell assay, and the expression levels of FBXO22, MMP-2, MMP-9 and MDM2 were detected by Western bolt. Results: After transfection with FBXO22 siRNA, the levels of FBXO22 in SW620 and HCT116 cells were significantly decreased, and the abilities of cell invasion and migration were decreased. Meanwhile, silencing of FBXO22 decreased expression of MMP-2, MMP-9, and increased expression of MDM2. Conclusion: FBXO22 can affect cell invasion and migration in colon cancer cells, and the mechanism may be related to the expression of MMP-2 and MMP-9.