Establishing therapeutic agents for the treatment of allergic diseases is an important focus of human health research. Sesamin, a lignan in sesame oil, exhibits a diverse range of pharmacological properties. However, to the best of our knowledge, the effect of sesamin on mast cell‑mediated allergic responses has not yet been investigated. Thus, the aim of the present study was to investigate the effect of sesamin on mast cell‑mediated allergic responses and the underlying mechanisms by which it produces this effect. In rats, oral administration of sesamin inhibited passive cutaneous anaphylaxis. Sesamin exposure attenuated immunoglobulin E‑induced histamine release from rat peritoneal mast cells, which was indicated to be mediated by the modulation of intracellular calcium. In human mast cells, sesamin reduced the stimulatory effects of phorbol 12‑myristate 13‑acetate and calcium ionophore A23187 on the production and secretion of pro‑inflammatory cytokines, including tumor necrosis factor‑α and interleukin‑6. The inhibitory effect of sesamin on pro‑inflammatory cytokine production was dependent on nuclear factor κ‑light‑chain‑enhancer of activated B cells (NF‑κB) and p38 mitogen‑activated protein kinase (MAPK). The present study demonstrates that sesamin inhibits mast cell‑derived inflammatory allergic reactions by blocking histamine release, and pro‑inflammatory cytokine production and secretion. In addition, the findings indicate that the effect of sesamin is mediated by its effect on p38 MAPK/NF‑κB signaling. Furthermore, the in vivo and in vitro anti‑allergic effects of sesamin reported in the present study suggest that it is a promising therapeutic agent for the treatment of inflammatory allergic diseases.