Allergic rhinitis (AR) is a type of respiratory disease closely associated with chronic inflammation. Esculetin is a natural coumarin derivative and has been reported to possess anti-allergic and anti-inflammatory effects. However, the roles of esculetin in AR have not been studied. In this study, we aimed to examine the effect of esculetin on AR using an in vitro model. The human nasal epithelial cells (HNEpC) were stimulated by histamine for 24hours with or without the pretreatment of esculetin. The mRNA levels and production of inflammatory cytokines including IL-6 and IL-8, as well as mucin 5AC (MUC5AC) were measured using qRT-PCR and ELISA, respectively. The results showed that esculetin suppressed histamine-induced expression and secretion of IL-6, IL-8, and MUC5AC in HNEpCs. Furthermore, we examined the effect of esculetin on NF-κB pathway by detecting the expression levels of NF-κB p65, p-p65 and IκBα using western blot analysis. Esculetin treatment suppressed the histamine-induced p-p65 expression and p-IκBα degradation. Inhibiting NF-κB pathway suppressed histamine-induced production of IL-6, IL-8, and MUC5AC in HNEpCs. These findings suggested that esculetin suppressed histamine-induced production of inflammatory cytokines and mucin in HNEpCs, which were partly mediated by the inhibition of NF-κB pathway.