Biomarkers predicting metastatic capacity might assist the development of better therapeutic strategies for aggressive cancers such as lung cancer. In this study, we show that adenylate kinase-4 (AK4) is a progression-associated gene in human lung cancer that promotes metastasis. Analysis of published microarray data showed that AK4 was upregulated in lung adenocarcinoma compared with normal cells. High AK4 expression was associated with advanced stage, disease recurrence and poor prognosis. Loss of AK4 expression suppressed the invasive potential of lung cancer cell lines, whereas AK4 overexpression promoted invasion in vitro and in vivo. Mechanistically, the transcription factor ATF3 was identified as a pivotal regulatory target of AK4. Simultaneous reduction in AK4 and ATF3 expression abolished the inhibitory effects of ATF3 on invasion. ATF3 overexpression in AK4-overexpressing cells limits invasion activity. Furthermore, patients with high AK4 and low ATF3 expression showed unfavorable outcomes compared with patients with low AK4 and high ATF3 expression. Taken together, our findings indicated that AK4 promotes malignant progression and recurrence by promoting metastasis in an ATF3-dependent manner.