Abstract: Objective MicroRNA is a class of small non-coding RNAs containing about 22 nucleotides, which has been implicated in many disease including tumors. miR-451 has been shown to be downregulated in several human malignancies and correlated with tumor progression. It has been demonstrated that miR-451 was significantly decreased in osteosarcoma tissues, and the patients with low miR-451 expression have shorter overall and disease-free survival. However, the underlying molecular mechanisms by which miR-451 contributes to osteosarcoma tumorigenesis have not been elucidated yet. Methods In the present study, the effect of miR-451 overexpression on invasion and epithelial-mesenchymal transition (EMT) of osteosarcoma was investigated. First, the lentivirus carrying miR-451 mimics were constructed and transfected into U2OS cells to elevate miR-451 expression. Wound healing test and Transwell assay were conducted to examine the effects of miR-451 overexpression on the migration and invasion of U2OS cells in vitro. Western blot assay was carried out to examine the EMT-associated proteins such as E-cadherin, Vimentin and transcription factor NF-κB. Results The miR-451 overexpression suppressed cell migration and invasion, up-regulated the expression of E-cadherin, down-regulated the expression of Vimentin, and down-regulated the expression of the expression of IKK-β. Conclusion The miR-451 may suppress the migration, invasion and EMT through inhibiting the activities of NF-κB.