Asthma, a heterogeneous disease of the airways, is common around the world, but little is known about the molecular mechanisms underlying the interactions between DNA methylation and gene expression in relation to this disease. The seeds of Descurainia sophia are traditionally used to treat coughs, asthma and edema, but their effects on asthma have not been investigated by multi-omics analysis. We undertook this study to assess the epigenetic effects of ethanol extract of D. sophia seeds (DSE) in an ovalbumin (OVA)-induced mouse model of asthma. We profiled genome-wide DNA methylation by Methyl-seq and characterized the transcriptome by RNA-seq in mouse lung tissue under three conditions: saline control, OVA-induced, and DSE-treated. In total, 1995 differentially methylated regions (DMRs) were identified in association with anti-asthmatic effects, most in promoter and coding regions. Among them, 25 DMRs were negatively correlated with the expression of the corresponding 18 genes. These genes were related to development of the lung, respiratory tube and respiratory system. Our findings provide insights into the anti-asthmatic effects of D. sophia seeds and reveal the epigenetic targets of anti-inflammatory processes in mice.