Background The overproduction of IgE plays a critical role in the pathogenesis of allergy; the mechanism is unclear. Histone‐acetyltransferase (HAT) activities are required in gene transcription of a large number of molecules in the immune system of the body. Objectives This study tests a hypothesis that HAT Tat‐interactive protein 60 (Tip60) plays an important role in the initiation of IgE‐mediated allergy. Methods The effects of Tip60 on regulating IgE expression were assessed with B cells. An intestinal allergy mouse model was developed to assess the role of Tip60 in the induction of IgE‐mediated allergic inflammation. Results High levels of Tip60 were observed in the peripheral B cells of patients with FA. Tat‐interactive protein 60 (Tip60) was required in the expression of IgE and IgG1 in B cells by inducing the chromatin remolding at the gene locus, in which histone acetylation, signal transducer and activator of transcription 6 (STAT6), and nuclear factor‐κB at the locus of Iε promoter were markedly increased. Blocking Tip60 significantly attenuated the allergic inflammation in the mouse intestinal mucosa. Conclusions Tat‐interactive protein 60 (Tip60) plays an important role in the induction of IgE in B cells. Blocking Tip60 inhibits the allergic inflammation in the intestine, suggesting Tip60 inhibitor may be a potential anti‐allergy drug.