The stress response gene activating transcription factor 4 (ATF4) is involved in metastatic behavior and cellular protection. Here we show that ATF4 is upregulated in osteosarcoma (OS) cell lines and patient clinical samples as compared to matched non-tumor tissue. Overexpression of ATF4 in OS cells promoted cell proliferation, migration and lung metastasis. Furthermore, the expression of ATF4 was markedly reduced in metastasis associated protein (MTA1) or histone deacetylase 1 (HDAC1) knockdown OS cells, but MTA1 overexpression increased the stability and activity of ATF4 protein via ATF4 deacetylation by HDAC1. ATF4 in turn enhanced the expression of MTA1 and HDAC1 at the transcription level, suggesting a positive feedback loop between ATF4 and MTA1/HDAC1. Clinically, the level of ATF4 was positively correlated with that of MTA1 in OS. Mice injected with ATF4-overexpressing cells exhibited a higher rate of tumor growth, and the average weight of these tumors was similar to 90% greater than the controls. Taken together, these data establish a direct correlation between ATF4-induced OS progression and MTA1/HDAC1-associated metastasis, and support the potential therapeutic value of targeting ATF4 in the treatment of OS.