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This study aims to elucidate the therapeutic effects and mechanisms of the combination of Epimedii Folium and Ligustri Lucidi Fructus on glucocorticoid(GC) synthesis-restricted asthma in rats. The classic asthma model induced by ovalbumin(OVA) sensitization and challenge, a complex asthma animal model with specific suppression of hypothalamic-pituitary-adrenal(HPA) axis at the synthesis level of endogenous GC by intraperitoneal administration of metyrapone(Met), was established. This model was designed to simulate the pathological condition of GC resistance or insufficient synthesis encountered in clinical practice. Male SD rats were randomly assigned into six groups: normal, Met, asthma+Met, Epimedii Folium, Ligustri Lucidi Fructus, and Epimedii Folium+Ligustri Lucidi Fructus, followed by a one-week drug treatment via gavage. Serum levels of corticotropin-releasing hormone(CRH), adrenocorticotropic hormone(ACTH), corticosterone(CORT), and cortisol(COR) were assessed. Targeted metabolomics was adopted to detect endogenous GC metabolism levels in the urine. Immunohistochemical staining was employed to assess the expression of hydroxysteroid dehydrogenase(HSD) 11B1,HSD11B2, cytochrome P450 family 11 subfamily B member 1(CYP11B1), and steroidogenic factor 1(SF1) in the lung and adrenal gland. Western blot was employed to quantify the expression of related proteins in the liver tissue. The results showed that Epimedii Folium and/or Ligustri Lucidi Fructus elevated the serum concentrations of CRH, ACTH, CORT, and COR in model rats, partially reversed abnormalities in the urinary GC metabolic profile, and upregulated the expression of key synthetic and metabolic enzymes(HSD11B1, HSD11B2, CYP11B1, and SF1) in the lung, liver, and adrenal gland. The combination of Epimedii Folium and Ligustri Lucidi Fructus exerts multi-faceted regulatory effects on both the HPA axis and GC synthesis/metabolism in the peripheral tissue, synergistically ameliorating endogenous GC dysregulation in synthesis-restricted asthma. These findings suggest the potential therapeutic value of this combination against GC resistance and related disorders.