Lung adenocarcinoma remains a threat to human health due to its high rate of recurrence and distant metastasis. However, the molecular mechanism underlying lung adenocarcinoma metastasis remains yet incompletely understood. Here, we show that upregulated expression of polypeptide N-acetylgalactosaminyltransferase6 (GALNT6) in lung adenocarcinoma is associated with lymph node metastasis and poor prognosis. In lung adenocarcinoma cells, GALNT6 over-expression promoted epithelial-mesenchymal transition (EMT), wound healing, and invasion which could be significantly reversed by GALNT6 silencing. GALNT6 silencing also mitigated the metastasis of lung adenocarcinoma and prolonged the survival of xenograft tumor-bearing mice. Furthermore, GALNT6 directly interacted with, and O-glycosylated chaperone protein GRP78, which promoted EMT by enhancing the MEK1/2/ERK1/2 signaling in lung cancer cells. Therefore, GALNT6 is emerging as novel positive regulator for the malignancy of human lung adenocarcinoma. Targeting GALNT6-GRP78-MEK1/2/ERK1/2 may thus represent a new avenue to develop therapeutics against lung cancer metastasis.