Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a multifaceted ligand-activated transcription factor that regulates inflammatory responses in asthma pathophysiology. The present study corroborates PPAR gamma-mediated anti-asthmatic action of the flavonoid, galangin (norizalpinin). In silico molecular interactions reveal that galangin formed three H-bonds (Glu291, Leu340 and Ser342) and a pi-sigma bond (Arg288) with PPAR gamma, contributing to the binding affinity and stability of the complex. In vivo studies explore the role of galangin as a propitious PPAR gamma agonist in mitigating airway inflammation, thereby excluding ligand-independent action of PPAR gamma. Accordingly, oral administration of galangin significantly ameliorated airway hyperresponsiveness, inflammation and goblet cell hyperplasia by the suppression of IL-4, 5, 13, 17, TNF-alpha, NO, ROS, EPO, IgE and increase of IFN-gamma in ovalbumin-induced allergic asthma model. PPAR gamma expression (mRNA and protein) studies were performed to elucidate a possible mechanism by which galangin modulates. Furthermore, to eliminate PPAR gamma-independent effects of galangin, a specific PPAR gamma antagonist (GW9662) was administered, which dramatically reversed the effects of galangin on PPAR gamma up-regulation, confirming the pleiotropic role of galangin as a PPAR gamma agonist in asthma therapeutics. Taken together, our findings communicate that PPAR gamma plays as a master regulator in the anti-asthmatic action of galangin. (C) 2020 Elsevier Inc. All rights reserved.