Electroconvulsive therapy (ECT) is a nonpharmacological treatment for depressive episodes and other psychiatric disorders. It is used to control the condition by causing a transient loss of consciousness through electrical stimulation. Dexmedetomidine (DEX) is a novel and highly selective adrenergic agonist with sedative, sympathetic nerve activity inhibiting and stress-responsive effects. This study focused on the effect of DEX on cerebral protection after ECT treatment. 68 depression patients were enrolled and divided into control group and DEX group. The occurrence of delirium after ECT treatment in depression cases was recorded. In vivo, we constructed chronic mild and unpredictable stress (CUMS) rats to mimic depression model. Meanwhile, ECT treatment and DEX injection were administrated in CUMS rats. Learning and memory in rats were measured by Morris water maze test, open field test (OFT), and forced swimming test (FST). Finally, the expression of miR-146a-5p and NF-kappa B was determined by RT-qPCR and western blot assay. The incidence of delirium after ECT treatment was prominently reduced in DEX group in relation to control group. In vivo, DEX injection had no effect on ECT treatment efficacy against depression conditions. After ECT treatment, the cognitive impairment was ameliorated in CUMS rats accomplished with decreased miR-146a-5p and increased NF-kappa B level. Finally, compared with ECT treatment, DEX injection could protect against depression-like behaviors by increasing miR-146a-5p level and inactivated NF-kappa B pathway. Overall, ECT-induced cognitive impairment in depression rats could be ameliorated by DEX injection via miR-146a-5p/NF-kappa B axis.