Th2 polarization is a key factor in the pathogenesis of allergic diseases, particularly airway allergy (AA). However, the mechanisms underlying the regulation of Th2 remain to be fully elucidated. Ethylisopropylamiloride (EIPA) has been shown to attenuate immune inflammation. This study aims to investigate the efficacy of EIPA in suppressing AA and to elucidate its underlying mechanisms. A mouse model of airway allergy was established to evaluate the effects of EIPA on AA. Additionally, bone marrow-derived dendritic cells (BMDCs) were generated to explore how EIPA modulates the properties of dendritic cells (DCs). We observed that administration of EIPA significantly alleviated experimental airway allergy. The expression of IL-12b in airway DCs was positively correlated with the suppressive effects of EIPA. Specifically, EIPA increased the levels of TRAF binding domain-containing protein (Trabid), a deubiquitinase, and Jmjd2d, a demethylase, at the IL-12b promoter region of DCs. These changes actively upregulated the expression of IL-12b. The elevated IL-12b subsequently led to the degradation of T cell immunoglobulin molecule domain-4 (TIM4) in DCs. Consequently, the Th2 response and airway allergy were mitigated. In conclusion, EIPA attenuates the allergic response by upregulating IL-12b production, reducing TIM4 expression in DCs, and suppressing the Th2 response.