ADAM-like decysin-1 (ADAMDEC1) has been reported to play an important role in the pathogenesis of multiple diseases, including cancers. However, its biological role in non-small cell lung cancer (NSCLC) remains largely unknown. Here, we aimed to investigate the biological functions and potential mechanism of ADAMDEC1 in NSCLC.We verified ADAMDEC1 as a DEG by a comprehensive strategy of TCGA and GEO datasets miming and computational biology. Relative levels of ADAMDEC1 in NSCLC tissues and the adjacent peritumoral tissues were identified by qRT-PCR, WB and IHC staining. The biological function of ADAMDEC1 was determined by CCK8, EdU, colony formation assay, apoptosis, wound healing migration and transwell invasion assays. Then, an in vivo tumor formation assay was conducted to explore the effects of ADAMDEC1 on tumor growth.The mRNA and protein expression levels of ADAMDEC1 were upregulated in NSCLC tissues and cell lines. ADAMDEC1 expression was associated with clinicopathological characteristics and overall survival of patients with NSCLC. Knockdown of ADAMDEC1 could decrease proliferation and colony forming ability of NSCLC cells, and promoted cell apoptosis, whereas ADAMDEC11 overexpression has opposite effects in NSCLC cells both in vivo and in vitro. Furthermore, we identified ADAMDEC1 accelerates NSCLC progression via activation of the PI3K/ AKT pathway.We verified that ADAMDEC1 promotes the progression of NSCLC via the PI3K/AKT pathway. These findings showed the potential of ADAMDEC1 to be used for therapeutic approaches in NSCLC.© 2022 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.