Background: Epithelial-mesenchymal transition (EMT) is responsible for metastasis of cancers, and NF-kappa B can promote tumor progression. Ezrin is an important molecule participating in EMT. However, whether Ezrin mediates NF-kappa B in EGF-induced osteosarcoma is unknown. Material/Methods: Ezrin phosphorylation, NF-kappa B activation, and EGF-induced EMT were studied in MG63 and U20S cells with NF-kappa B inhibition, silencing, or over-expressing Ezrin. Cell morphology, proliferation, migration, and motility were analyzed. An osteosarcoma model was established in mice by injecting MG63 and U20S and reducing Ezrin. Results: With EGF induction in vitro, Ezrin Tyr353 and Thr567 were phosphorylated, and EMT, proliferation, migration, and motility of osteosarcoma cells were promoted. Silencing Ezrin suppressed and over-expressing Ezrin promoted the nuclear translocation of p65 and phosphorylated I kappa B alpha (p-I kappa B alpha) in EGF-induced osteosarcoma cells. NF-kappa B inhibitor blocked EGF-induced EMT in both cell types, as well as reserving cell morphology and suppressing proliferation, migration, and motility. In vivo, reducing Ezrin significantly suppressed metastasis of osteosarcoma xenografts, increased liver and lung weights, and activated NF-kappa B, which were both induced by EGF. Conclusions: Ezrin/NF-kappa B regulated EGF-induced EMT, as well as progression and metastasis of osteosarcoma in vivo and in vitro. Ezrin/NF-kappa B may be a new therapeutic target to prevent osteosarcoma from deterioration.