Cell adhesion molecule 4 (CADM4) is downregulated in many human cancers. However, CADM4 expression levels in human non-small cell lung cancer (NSCLC) tissues and its roles in NSCLC progression remain unknown. Our study aims to address these issues. We examined CADM4 levels in NSCLC tissues using real-time PCR and western blot. A549 and NCI-H1299 cells were then transfected with pcDNA3.1-CADM4 plasmid or siCADM4 to overexpress or knock down CADM4. Cell proliferation, cell cycle distribution, migration, and invasion were evaluated. NSCLC cells transfected with pcDNA3.1-CADM4 plasmid or siCADM4 were treated with SC79 or LY294002, respectively, to investigate the involvement of the Akt signaling pathway. Male nude mice were subcutaneously injected with stably transfected cells (1 × 10 cells/mice) to observe tumor growth. Stably transfectants were injected into nude mice (1 × 10 cells/mice) via tail vein to observe tumor metastasis. The results showed that CADM4 gene and protein levels in NSCLC tissues were significantly lower than those in corresponding adjacent tissues. CADM4 overexpression markedly inhibited cell proliferation, migration, and invasion. We also found that matrix metalloproteinase 9 (MMP-9) and MMP-2 activities were reduced. Moreover, CADM4 overexpression arrested the cell cycle at G1 phase, with the changes in expression of cell cycle regulators. The Akt signaling pathway was inhibited by CADM4 overexpression. In contrast, CADM4 knockdown showed the opposite effects. Additionally, SC79 and LY294002 reversed the effects of CADM4 overexpression and CADM4 knockdown in vitro, respectively. In xenograft models, CAMD4 overexpression suppressed, while CADM4 knockdown promoted tumor growth, accompanied by changes in Ki67 expression. In in vivo metastasis assay, CADM4 overexpression decreased, while CADM4 knockdown increased numbers of metastatic nodules in lung and liver. These evidences suggest that CADM4 may regulate NSCLC progression via the Akt signaling pathway. CADM4 may be a potential therapeutic target for NSCLC.Copyright © 2020. Published by Elsevier Ltd.