Simultaneous exposure to both BaP and house dust mites (HDM) has been shown to exacerbate pulmonary inflammation and hyperresponsiveness in a murine asthma model. The mechanistic insight into epigenetic inheritance for this effect, however, remains to be clarified. As such, in this study, we explore the molecular basis for the enhancement of asthma. Female BAL/C mice were intranasally administered HDM (25 µg in 25 μL saline) and/or BaP (10 μg/kg) every other day for 9 weeks. RNA sequencing and DNA methylation assessment were used to explore the underlying mechanism. Following simultaneous exposure to HDM and BaP, mice exhibited pulmonary inflammation and the transcript level of IL4i1b, muc4 and IL22ra2 that were associated with altered DNA methylation, suggesting that there may be an epigenetic basis for BaP-induced asthma exacerbation. Our data suggest that DNA methylation is a major epigenetic modification that accompanies airway remodeling associated with changes in the allergic mice.