Recent evidence suggests that T-box transcription factor brachyury plays an important role in lung cancer development and progression. However, the mechanisms underlying brachyury-driven cellular processes remain unclear. Here we found that fibroblast growth factor receptor 1/mitogen-activated protein kinase (FGFR1/MAPK) signaling regulated brachyury in lung cancer. Analysis of FGFR1-4 and brachyury expression in human lung tumor tissue and cell lines found that only expression of FGFR1 was positively correlated with brachyury expression. Specific knockdown of FGFR1 by siRNA suppressed brachyury expression and epithelial-mesenchymal transition (EMT) (upregulation of E-cadherin and β-catenin and downregulation of Snail and fibronectin), whereas forced overexpression of FGFR1 induced brachyury expression and promoted EMT in lung cancer cells. Activation of fibroblast growth factor (FGF)/FGFR1 signaling promoted phosphorylated MAPK extracellular signal-regulated kinase (ERK) 1/2 translocation from cytoplasm to nucleus, upregulated brachyury expression, and increased cell growth and invasion. In addition, human lung cancer cells with higher brachyury expression were more sensitive to inhibitors targeting FGFR1/MAPK pathway. These findings suggest that FGFR1/MAPK may be important for brachyury activation in lung cancer, and this pathway may be an appealing therapeutic target for a subset of brachyury-driven lung cancer.