Severe asthma imposes a physical and economic burden on both patients and society. As chromatin regulators (CRs) influence the progression of multiple diseases through epigenetic mechanisms, we aimed to study the role of CRs in patients with severe asthma. Transcriptome data (GSE143303) from 47 patients with severe asthma and 13 healthy participants was downloaded from the Gene Expression Omnibus database. Enrichment analysis was performed to investigate the functions of differentially expressed CRs between the groups. We identified 80 differentially expressed CRs; they were mainly enriched in histone modification, chromatin organization, and lysine degradation. A protein–protein interaction network was then constructed. The analyzed immune scores were different between sick and healthy individuals. Thus, CRs with a high correlation in the immune analysis,SMARCC1,SETD2,KMT2B,and CHD8, were used to construct a nomogram model. Finally, using online prediction tools, we determined that lanatoside C, cefepime, and methapyrilene may be potentially effective drugs in the treatment of severe asthma. The nomogram constructed using the four CRs,SMARCC1,SETD2,KMT2B, andCHD8, may be a useful tool for predicting the prognosis of patients with severe asthma. This study provided new insights into the role of CRs in severe asthma.