Citrus nippokoreana, a Korean native citrus species, has traditionally been used to alleviate respiratory inflammation and is abundant in bioactive compounds such as flavonoids and polyphenols. In this study, a 30% ethanol extract from its peel (CNE) was prepared and evaluated for its cognitive benefits in vitro and in vivo. In vitro, HT22 cells were pretreated with CNE before L-glutamic acid exposure to induce oxidative stress. CNE increased cell viability and reduced ROS levels. Western blot showed reduced apoptosis and activation of AKT/Nrf2 and BDNF/TrkB pathways. In vivo, memory impairment was induced by scopolamine, followed by oral CNE administration (100 or 200 mg/kg/day). CNE-treated mice showed improved memory in NOR, Y-maze, and PAT tests. In hippocampal and cortical tissues, CNE increased markers of synaptic plasticity (TrkB, BDNF, CREB) and antioxidant activity (Nrf2, HO-1), and decreased AChE levels, suggesting enhanced cholinergic neurotransmission. Nissl staining confirmed preserved neuronal structure, and PathoGreen staining showed reduced fluorescence in the hippocampus, indicating protection from neuronal damage. These findings suggest that CNE exerts neuroprotective effects by reducing oxidative stress, enhancing synaptic plasticity, and improving cholinergic function, supporting its potential as a functional food or therapeutic agent for cognitive protection.