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Vaccinium bracteatum Thunb. Leaves (VBL) are a component of traditional herbal medicines. However, molecular mechanisms of VBL in stress-related memory impairment are still unclear. This study aimed to investigate the spatial memory improvement effects of VBL in an animal model of chronic restraint stress (CRS) by using Y maze test and identified possible protective mechanisms against oxidative stress inducers (e.g., corticosterone and hydrogen peroxide [H2O2]) in SH-SY5Y neuronal cells. VBL showed neuroprotective effects via reduced release of lactate dehydrogenase (LDH) in corticosterone or H2O2-induced cell death that was mediated through the regulation of cleaved caspase-3 and Nrf2 pathways. Furthermore, CRS-exposed mice were orally administered VBL (10, 50, 100, and 200 mg/kg) daily for 21 days. CRS-exposed mice treated with VBL showed significantly increased spontaneous alternation in short-term memory (STM) and long-term memory (LTM) trials, and number of total arm entries in LTM trials as measured by the Y maze test. Moreover, VBL (50, 100, and 200 mg/kg) decreased acetylcholinesterase (AChE) activity in the hippocampus (HC, [Formula: see text] ¡ 0.01 and [Formula: see text] ¡ 0.001, respectively) and prefrontal cortex (PFC). CRS-exposed mice treated with VBL had dramatically decreased total Tau and Tau phosphorylation in the synapse of the HC and PFC which might be mediated by the regulation of CaMKII and GSK3[Formula: see text] phosphorylation. Additionally, VBL reduced CRS-induced upregulation of N-methyl-D-aspartate (NMDA) receptor subunits (NMDAR1, 2A, and 2B). Thus, VBL exerts spatial memory improvement by regulating CRS-induced NMDA receptor neurotoxicity and Tau hyperphosphorylation.