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Objective: To study the effect of total flavonoids of Rhizoma Drynariae on the expression of NMDAR1, GluR2 and CAMK II protein in model mice of kidney deficiency induced by exogenous glucocorticoid hydrocortisone and its mechanism. Methods: Kunming (KM) mice were randomly divided into the blank group, the hydrocortisone model group, the anti-brain failure capsule group, the Drynaria total flavonoids group, the Drynaria total flavonoids+ER blocker group, with 15 animals in each group. Except for the blank group, all groups were injected intramuscularly with hydrocortisone (25 mg·kg-1·d-1) to create models. The water maze experiment, new object recognition experiment and platform jump experiment were used to conduct behavioral investigations. HE staining was used to observe the pathological changes of mouse hippocampus, and Western blotting detected the expressions of NMDR1, GluR2 and CAMK II proteins in the hippocampus of mice in each group. Results: The experimental results showed that compared with the model group, the learning and memory ability of the mice in the Drynaria fortunei total flavonoids group was significantly improved, and the difference was statistically significant (P <0.01), the expression of NMDR1 and GluR2 proteins in the hippocampus of the mice was significantly increased (P<0.01), and the level of CAMK II protein significantly decreased (P<0.01). Conclusion: The total flavonoids of Rhizoma Drynariae may enhance the expression of NMDAR1 and GluR2 protein in the brain of hydrocortisone model mice through ER, reduce the expression of CAMK II protein, and alleviate the damage to the brain tissue of the model mice and play a neuroprotective effect. [ABSTRACT FROM AUTHOR]