In the present study, we demonstrated that OVA-induced allergic airway inflammation occurred in parallel with increased-expression of TLR2, activation of NLRP3 inflammasome and decreased biosynthesis of melatonin. Deletion of TLR2 effectively alleviated allergic airway inflammation and concomitantly inhibited the activation of NLRP3 inflammasome as well as restored the level of melatonin. Furthermore, exogenous addition of melatonin to OVA-challenged WT mice pronouncedly ameliorated airway inflammation, decreased OVA-induced TLR2 expression and NLRP3 activity, and increased melatonin biosynthesis to similar level as that in OVA-challenged TLR2−/− mice. However, although luzindole significantly reduced the expression of AANAT and ASMT and subsequent level of melatonin in OVA-challenged TLR2−/− mice, it exhibited null effect on OVA-induced airway inflammation and activation of NLRP3, it only aggravated allergen-induced mucus hyper-secretion. These results are the first to show the existence of TLR2-melatonin feedback loop in allergic airway diseases, which regulates NLRP3 inflammasome activity and may represent a mechanism underlying the initiation and persistence of airway inflammation.