Nevadensin (NEV), a natural flavonoid compound derived from Lysionotus pauciflorus Maxim, has numerous biological activities. However, few researchers have examined its potential impact on alleviating allergies. In the present study, NEV was found to upregulate rectal temperature, suppress the development of diarrhea, and decrease the levels of serum specific immunoglobulin E, histamine and mouse MC protease-1 in ovalbumin-allergic mice. Moreover, NEV also alleviated passive cutaneous anaphylaxis reactions and inhibited the release of β-hexosaminidase and histamine in bone marrow-derived mast cells. Furthermore, we provide the first demonstration that NEV decreases the expression of c-Kit and suppresses the proliferation of bone marrow-derived mast cells and accelerates their apoptosis. These findings indicated that L. pauciflorus-derived NEV might have the potential to alleviate food hypersensitivity.