Objective To investigate the role and mechanism of ORMDL3 in neutrophil asthma through endoplasmic reticulum stress ( ERS)-mediated autophagy. Methods Adult male SD rats were randomly divided into control, model, model+NC siRNA, model+ORMDL3 siRNA, solvent control, model+solvent control, model+NC siRNA group+ solvent control, model + ORMDL3 siRNA + solvent control and model + ORMDL3 siRNA + agonist groups. The neutrophil asthma model was established by lipopolysaccharide and ovalbumin sensitization. An ORMDL3 siRNA lentivirus or negative control (NC)-siRNA lentivirus was administered through the airway and ERS agonist, carotene, or solvent was injected intraperitoneally. Airway function, 0. 2 s forced expiratory volume (FEV0. 2) / forced vital capacity (FVC), peak expiratory flow ( PEF), pathological changes of lung tissue and the expression levels of ORMDL3, ERS marker genes PERK, IRE1α, ATF6 and autophagy marker genes Beclin-1 and LC3 were analyzed. Results FEV0. 2 / FVC and PEF levels of the model group were lower than those of the control group and the expression levels of ORMDL3, PERK, IRE1α, ATF6, Beclin-1 and LC3-II/ LC3-I in lung tissue were higher than those of the control group (P<0.05). FEV0. 2 / FVC and PEF levels of the model+ORMDL3-siRNA group were higher than those of the model+NC-siRNA group and the expression levels of ORMDL3, ATF6, Beclin-1 and LC3-II/ LC3-I in lung tissue were lower than those of the model+NC-siRNA group (P<0. 05). The expression levels of PERK and IRE1α showed no difference compared with the model+NC-siRNA group (P> 0.05). FEV0. 2 / FVC and PEF levels in the model+ORMDL3 siRNA+agonist group were lower than those in the model +ORMDL3 siRNA+solvent group and the expression levels of Beclin-1 and LC3-II/ LC3-I in lung tissue were higher than those in the control group ( P< 0.05 ). Conclusions In the pathogenesis of neutrophil asthma, ORMDL3-induced autophagy through ERS ATF6 pathway is a possible molecular mechanism. Blocking ORMDL3 is a possible treatment method for neutrophil asthma.