Histone demethylase UTX has been reported to participate in the occurrence and development of many cancers in tissue-specific manners. However, the role of UTX in non-small cell lung cancer (NSCLC) and exactly what regulates the expression of UTX remains unclear. Here, we analyzed the role of UTX in NSCLC in association with the widely recognized tumor driver epidermal growth factor receptor (EGFR).UTX levels in clinical samples were detected by immunohistochemistry staining, western blotting and real-time quantitative PCR. The expression of UTX in tumor tissue was correlated with the phosphorylation of EGFR. Cell proliferation and migration were evaluated by MTT and wound-healing assays. The impact of EGFR and its downstream pathways on UTX was explored with corresponding inhibitors, and examined by western blotting and real-time quantitative PCR.In this study, we found that the expression of UTX in cancer tissues of patients with NSCLC was significantly higher than that in paracancerous tissues, and positively associated with EGFR phosphorylation levels. In addition, in NSCLC cell lines, UTX can promote proliferation and migration, while inhibition of its enzyme activity suppressed cell growth. Moreover, UTX expression was significantly upregulated when EGFR signaling pathway was activated, and vice versa when EGFR pathway was inhibited by tyrosine kinase inhibitor. Further mechanistic studies suggested that the activation of EGFR activated its downstream JAK/STAT3 signaling pathway and promoted STAT3 phosphorylation; the phosphorylated STAT3 transcriptionally promoted the levels of UTX.These results suggest an "EGFR-STAT3-UTX" axis that plays an oncogenic role in NSCLC.© 2021. The Author(s).