Objective To screen the key genes in childhood therapy-resistant asthma by bioinformatic method, and to verify its expression and diagnostic value in peripheral blood of children with therapy-resistant asthma. Methods The transcriptome dataset GSE27011 of peripheral blood mononuclear cells from healthy children (healthy control group), mild asthma (MA) children (MA group) and severe asthma (SA) children (SA group) was downloaded from the Gene Expression Omnibus of the National Center for Biotechnology Information of the United States. Key genes were obtained by using R software for gene differential expression analysis, weighted gene co-expression network analysis (WGCNA) and clinical phenotypic correlation analysis. The differential expression levels of key genes were verified in children with asthma and immune cell transcriptome datasets. Seventy-eight children with asthma and 30 healthy children who were diagnosed in the Department of Pediatrics of Tangshan People’s Hospital between September 2020 and September 2021 were selected and divided into control group, MA group and SA group. Peripheral blood samples from children with asthma and healthy children who underwent physical examination were collected to detect the expression levels of key genes and inflammatory factors interleukin (IL)-4 and IL-17 in peripheral blood of children. Receiver operating characteristic curve was used to evaluate the sensitivity, specificity and accuracy of key genes in predicting childhood therapy-resistant asthma. Results The key gene GNA15 was obtained by bioinformatic analysis. Analysis of asthma validation dataset showed that GNA15 was up-regulated in asthma groups, and was specifically expressed in eosinophils. Clinical results showed that the expression levels of IL-4, IL-17 and GNA15 among the three groups were significantly different (P<0.05). The expression levels of IL-4 and IL-17 in the MA group and the SA group were higher than those in the control group (P<0.05). Compared with the control group and the MA group, the expression level of GNA15 in the SA group was up-regulated (P<0.05). Neither the difference in the expression level of IL-4 or IL-17 between the MA group and the SA group, nor the difference in the expression level of GNA15 between the control group and the MA group was statistically significant (P>0.05). The specificity, sensitivity and accuracy of GNA15 in predicting SA were 92.90%, 80.00% and 86.10%, respectively. Conclusion GNA15 has a significant clinical value in predicting the childhood therapy-resistant asthma, and may become a potential diagnostic marker for predicting the severity of asthma in children.