BackgroundHypoxia contributes to the development of invasive and metastatic cancer cells, and is detrimental to cancer treatment. This study aimed to explore the molecular mechanisms by which hypoxic microenvironments affect hypoxic non-small cell lung cancer (NSCLC) development and the effects of M2 macrophage-derived extracellular vesicles (EVs) on NSCLC cells.MethodsA549 cells were cultured in an anoxic incubator for 48 h to construct hypoxic A549 cells, and then normal and hypoxic A549 cells were harvested for RNA sequencing. Next, THP-1 cells were used to induce M2 macrophages, and EVs were isolated from THP-1 cells and M2 macrophages. Cell counting kit-8 and transwell assays were used to determine the viability and migration of hypoxic A549 cells, respectively.ResultsAfter sequencing, 2426 DElncRNAs and 501 DEmiRNAs were identified in normal A549 cells and hypoxic A549 cells. These DElncRNAs and DEmiRNAs were significantly enriched in “Wnt signaling pathway,” “Hippo signaling pathway,” “Rap1 signaling pathway,” “calcium signaling pathway,” “mTOR signaling pathway,” and “TNF signaling pathway.” Subsequently, ceRNA networks consisting of 4 lncRNA NDRG1 transcripts, 16 miRNAs and 221 target mRNAs were built, and the genes in the ceRNA networks were significantly associated with “Hippo signaling pathway” and “HIF-1 signaling pathway.” EVs were successfully extracted from THP-1 cells and M2 macrophages, and M2 macrophage-derived EVs significantly enhanced the viability and migration of hypoxic A549 cells. Finally, M2 macrophage-derived EVs further upregulated the expression of NDRG1-009, NDRG1-006, VEGFA, and EGLN3, while downregulating miR-34c-5p, miR-346, and miR-205-5p in hypoxic A549 cells.ConclusionsM2 macrophage-derived EVs may worsen the progression of NSCLC in a hypoxic microenvironment by regulating the NDRG1-009-miR-34c-5p-VEGFA, NDRG1-006-miR-346-EGLN3, NDRG1-009-miR-205-5p-VEGFA, and Hippo/HIF-1 signaling pathways.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12890-023-02468-7.