Allergic diseases are a group of allergen-induced unfavorable immune responses initiating various symptoms in different organs. Mas-related G protein-coupled receptor X2 (MRGPRX2) on mast cells has been reported to be responsible for immunoglobulin E (IgE)-independent immune diseases and allergic drug reactions and has therefore been a crucial drug target for the development of anti-pseudo-allergic agents. Considering the active structural features of MRGPRX2, we designed and synthesized a series of diaryl ureas (DPUs). DPUs exert promising potency for inhibiting β-hexosaminidase release in LAD2 cells with half-maximal inhibitory concentrations (IC<sub>50</sub>) values of 2.51-0.62 μM, as well as favorable antilocal and systemic anaphylaxis in mice at a dosage of 10 mg/kg. MRGPRX2 is further revealed to participate in the anti-pseudo-allergic activity of DPUs by binding with electrophilic urea and trifluoromethyl substituents. In brief, these results highlight entities with powerful electrophilic substituents as a prospective therapeutic strategy for the treatment of IgE-independent disorders.