Background and aims The function of interleukin (IL)‐10‐producing B cells (B10 cell) is compromised in patients with allergic diseases. Protease‐activated receptor (PAR)‐2 has immunoregulatory functions. This study aimed to elucidate the role of PAR2 in the suppression of IL‐10 expression in peripheral B cells. Methods Peripheral blood B cells were collected from patients with allergic rhinitis (AR). A correlation between the expression of Bcl2‐like protein 12 (Bcl2L12) and IL‐10 in the B cells was analyzed. An AR mouse model was developed. Results We observed that the expression of IL‐10 was lower in the peripheral B cells from patients with airway allergy. A negative correlation was identified between the expression of IL‐10 and PAR2 in B cells. Activation of PAR2 of B cells increased the expression of Bcl2L12 and suppression of LPS‐induced IL‐10 expression, which were inhibited by knocking down the Bcl2L12 gene. Treating B cells from AR patients with Bcl2L12‐shRNA‐carrying liposomes reversed the capability of IL‐10 expression and the immunosuppressive function. Administration of Bcl2L12 shRNA‐carrying liposomes attenuated experimental AR in mice. Conclusions Activation of PAR2 inhibits the expression of IL‐10 in B cells, which can be reversed by treating B cells with Bcl2L12 shRNA‐carrying liposomes. The data suggest that regulation of Bcl2L12 may be a novel approach in the treatment for AR.