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ETHNOPHARMACOLOGICAL RELEVANCE Diabetes is a systemic disease, which can cause synaptic defects in the hippocampus. Hippocampus plays a crucial role in learning and memory. Melissa officinalis L. has been used as for memory enhancement in Persian Medicine. AIM OF THE STUDY The aim of this study was to evaluate the impact of the hydroalcoholic extract of Melissa officinalis L. on learning and memory, considering its impact on nitric oxide synthase and brain-derived neurotrophic factor expression in the hippocampus of diabetic rats. MATERIALS AND METHODS Melissa officinalis L. extract was obtained by maceration method. To evaluate phenolic and flavonoid compounds of the extract, the samples were analyzed by HPLC. The animals were randomly divided into 6 groups: vehicle-treated control, Melissa officinalis-treated control (50 mg/kg), vehicle-treated diabetic, and M. officinalis-treated diabetic (25, 50, or 100 mg/kg). Diabetes was induced by streptozotocin And Melissa officinalis L. was administered for 2 weeks once diabetes was induced. Passive avoidance and Y-maze tasks were performed for learning and memory assessment. At the end of learning and memory tasks, rats were sacrificed and their hippocampus removed, lysed, and homogenized. The RNA contents were purified and then used as the template for cDNA synthesis. Real-time PCR was used to evaluate nitric oxide synthase and brain-derived neurotrophic factor genes expression. RESULTS Rutin was main flavonoid compound and rosmarinic acid was the main phenolic compound of the Melissa officinalis extract. Streptozotocin induced diabetes and impaired learning and memory in diabetic rats. Melissa officinalis treated-control group showed a higher alternation score in the Y-maze task and step-through latency in the passive avoidance task compared to the vehicle treated diabetic group. Melissa officinalis-treated rats showed a higher alternation score in the Y-maze task in all doses compared to the vehicle treated diabetic group (P<0.05). In addition, in the passive avoidance task Melissa officinalis increased step-through latency (P<0.05) but not initial latency, in all doses. Furthermore, in diabetic rats, the expression of brain-derived neurotrophic factor and nitric oxide synthase genes decreased. However, hippocampal brain-derived neurotrophic factor and nitric oxide synthase gene expression was increased in Melissa officinalis-treated rats compared to diabetic rats (P<0.05). CONCLUSIONS Melissa officinalis improved learning and memory in diabetic rats, which may have occurred by increasing brain-derived neurotrophic factor and nitric oxide synthase gene expression.