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Advanced osteosarcoma (OS) is usually treated by preoperative and postoperative chemotherapy, but there are a very limited number of active agents. Celecoxib (Cel) is a COX-2-selective nonsteroidal anti-inflammatory drug and its antitumoral effect has been shown widely in a variety of cancers including OS cells in vitro. However, the potential combinational effect of Cel with other biological therapy has not been reported in OS cells. In this study, the effects of Cel, miR-34a mimics, and their combination on cell proliferation (MTT assay), migration (in-vitro scratch assay), invasion (transwell assay), mRNA (real-time PCR), and protein (Western blot) expression of associated signal transductions were investigated in cultured MG63 cells. The results showed that miR-34a mimics transfection and Cel treatment significantly decreased cell viability, migration, and invasion in MG63 cells, with their combination being more effective. In contrast, miR-34a inhibitors transfection exerted an effect opposite to miR-34a mimics on cell viability, migration, and invasion. The antitumoral effects of miR-34a, Cel, and their combination were observed in significant up-regulated expression of PTEN and GSK-3β, down-regulated expression of ROCK1, Notch1, and MMP9 as well as Akt Ser473 phosphorylation. Our data suggested that miR-34a exerts a combinational effect with Cel on the cell proliferation, migration, and invasion in OS cells through regulating Notch1/ROCK1–PTEN–Akt–GSK-3β signaling and MMP9 gene expression.