Objective To explore the effects of 1α,25-dihydroxyvitamin D₃ on airway inflammation in asthmatic mice and the potential mechanisms. Methods Twenty-four female BALB/c mice in SPF grade were randomly divided into three groups (n=8): control group, asthma group, and asthma+VD₃ group. On the 1st, 8th, and 15th day, asthma group and asthma+VD₃ group were given 0.2 ml ovalbumin (OVA) suspension for sensitization, while control group received 0.2 ml normal saline. On the 22-28th day, asthma group and asthma+VD₃ group were challenged with 1% OVA atomization inhalation, while control group received an equal amount of normal saline atomization, for 30 minutes each time, once a day, for a continuous 7 days. Asthma+VD₃ group was given intraperitoneal injection of 1α,25-dihydroxyvitamin D₃ injection (4 μg/kg) 30 minutes before each atomization, while control group and asthma group were given an equal dose of normal saline. After the last challenge, all mice were anesthetized, and serum, bronchoalveolar lavage fluid (BALF) and lung tissue samples were collected. HE staining and Periodic Acid Schiff (PAS) staining were used to observe the pathological changes in lung tissue and changes in airway mucus levels. ELISA was employed to detect serum IgE and inflammatory cytokines IL-4, IL-5 and IL-13 in BALF. Immunohistochemical technique and Western blotting were used to detect the expressions of SIRT1 and GATA-3 in mouse lung tissue. Results Compared with control group, asthma group had a significant increase in inflammatory cell infiltration around lung tissue, bronchia and accompanying perivascular, mainly characterized by eosinophils. Bronchial lumen stenosis, airway mucosal epithelial hyperplasia, and increased tracheal mucus secretion were also observed. The above changes in asthma+VD₃ group were reduced compared with asthma group. Compared with control group, serum levels of IgE, and IL-4, IL-5, IL-13 inflammatory factors in BALF and GATA-3 in lung tissue were increased in asthma group (P<0.05), and SIRT1 level in lung tissue was significant decreased (P<0.05). Compared with asthma group, IgE level in serum, inflammatory factors of IL-4, IL-5 and IL-13 in BALF, and GATA-3 in lung tissue in asthma+VD₃ group were decreased (P<0.05), and SIRT1 level in lung tissue was increased (P<0.05). Correlation analysis showed that the expression level of lung tissue SIRT1 was negatively correlated with the expression of GATA-3, serum IgG, and the levels of IL-4, IL-5, and IL-13 in BALF (P<0.05); the expression level of lung tissue GATA-3 was positively correlated with serum IgG and the levels of IL-4, IL-5, and IL-13 in BALF (P<0.05). Conclusion 1α,25-dihydroxyvitamin D₃ can alleviate airway inflammation in asthmatic mice, possibly by upregulating the expression of SIRT1 in lung tissue and inhibiting the expression of GATA-3, thereby inhibiting inflammatory factors (IL-4, IL-5, IL-13).