Cuproptosis, a copper-dependent cell death mechanism, has emerged as a novel regulator of asthma progression. We investigated the expression of cuproptosis-related genes during the occurrence and progression of asthma, elucidated their correlation with inflammatory immunity and gut microbiota, and explored novel asthma pathogenesis mechanisms. Using the GSE64913 asthma dataset from the Gene Expression Omnibus (GEO), we performed Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Set Enrichment Analysis (GSEA), Weighted Gene Co-Expression Network Analysis (WGCNA), and immune cell infiltration investigations to identify 13 cuproptosis-related differentially expressed genes (CuDEGs). An ovalbumin-induced mouse asthma model revealed exacerbated airway inflammation and elevated IL-5, IgE, and copper levels. Quantitative Real-time polymerase chain reaction (qRTPCR) and Western Blot (WB) confirmed the downregulation of iron sulfur cluster protein FDX1, LIAS, ACO2, ETFDH, NDUFV1, mitochondrial proteins DLAT and DLST, and several CuDEGs in the OVA group, including ATP7A, CP, SLC31A1. Furthermore, high-throughput mRNA and 2bRAD-M microbial sequencing revealed correlations between CuDEGs expression profiles, inflammatory immune signatures, and gut microbiota composition. Collectively , our study demonstrates that cuproptosis modulates airway inflammation in asthma. CuDEGs participate in immune regulation and inflammatory response through the gut microbiota-cuproptosis-asthma axis, supporting the gut-lung axis theory and providing insights into asthma pathogenesis.