AbstractAstrocyte elevated gene‐1 (AEG‐1) plays a critical role in the development, progression, and metastasis of a variety of cancers, including non‐small–cell lung cancer (NSCLC). The objective of the current study is to unravel the upstream signaling of AEG‐1. A cohort of 28 NSCLC tissues and 30 normal tissues were collected. Quantitative reverse transcription‐polymerase chain reaction and Western blotting were used to examine AEG‐1, migration, and invasion related markers in NSCLC cells. 3‐(4,5‐Dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assay coupled with colony formation assay were conducted to monitor cell growth. Transwell assay was performed to determine cell migration and invasion. Apoptotic cells were detected by costaining with Annexin‐V‐fluorescein isothiocyanate and propidium iodide. Immunofluorescent staining was used to observe the levels of migration and invasion related markers. Xenograft models were used to investigate tumor formation in vivo. Dual‐luciferase reporter assay and RNA immunoprecipitation were carried out to determine the interaction between circMTDH.4 and miR‐630, as well as the associated between miR‐630 and AEG‐1. AEG‐1 was highly expressed in NSCLC tissues and cell lines. Silencing of AEG‐1 inhibited cell proliferation, migration, invasion, and chemoresistance/radioresistance in NCI‐H1650 and A549 cells. circMTDH.4 regulated AEG‐1 expression via sponging miR‐630. Knockdown of circMTDH.4 and/or overexpression of miR‐630 inhibited chemoresistance and radioresistance in NSCLC cells, whereas overexpression of AEG‐1 or knockdown of miR‐630 exerted rescue effects. circMTDH.4/miR‐630/AEG‐1 axis is responsible for chemoresistance and radioresistance in NSCLC cells.