Chronic exposure to high-altitude hypoxia impairs hippocampus-dependent learning and memory. However, the upstream mitochondrial mechanisms by which oxygen deficiency triggers synaptic dysfunction remain incompletely understood. Therefore, the present study aimed to investigate the role of tumor necrosis factor receptor-associated protein 1 (TRAP1), a mitochondria-restricted chaperone, in this pathological process. In vivo, adult male Sprague-Dawley rats were exposed to a hypobaric chamber simulating an altitude of 5,000 m for 28 days. In vitro, HT22 hippocampal neurons were exposed to 1% oxygen (O₂) for 48 h to establish hypoxic cell models. TRAP1 was overexpressed using lentivirus or pharmacologically activated by a selective WNT5a agonist. Hippocampal structure and cognitive function were evaluated using the Morris Water Maze test for cognitive function assessment, high-resolution magnetic resonance imaging (MRI) for hippocampal volumetric and structural analysis, and whole-cell patch-clamp for neuronal recording. Moreover, the following series of experiments was conducted: transmission electron microscopy (TEM) for ultrastructural characterization of mitochondria–endoplasmic reticulum (ER) contact sites (MERCS), fluorometric assays for intracellular calcium (Ca²⁺) and reactive oxygen species (ROS) detection, reverse transcription quantitative PCR for mitochondrial DNA (mtDNA) integrity and gene expression quantification, and western blotting and co-immunoprecipitation analysis to assess the expression of synaptic-related proteins and their interactions. Hypoxia exposure led to a significant downregulation of hippocampal TRAP1 and WNT5a expression. It also caused a reduction in the MERCS gap width, a three-fold increase in mitochondrial ROS production, a two-fold elevation in mitochondrial matrix Ca²⁺ concentration, a 50% decrease in mtDNA copy number, and significant reductions in the expression of brain-derived neurotrophic factor, doublecortin, and postsynaptic density protein 95. These pathological changes were accompanied by decreased platform crossings in the Morris water maze test and loss of hippocampal definition on MRI. Notably, Trap1 overexpression reversed these hypoxia-induced deficits: it restored MERCS gap width, normalized redox balance and intracellular Ca²⁺levels, promoted transcription factor A mitochondrial-dependent mtDNA synthesis, recovered synaptic protein expression levels, and ultimately ameliorated neurodevelopmental impairment. In contrast, Trap1 knockdown recapitulated the hypoxic injury phenotypes. Additionally, treatment with a WNT5a agonist significantly upregulated TRAP1 expression, inhibited dynamin-related protein 1-mediated mitochondrial fission, and exerted a neuroprotective effect against hypoxia-induced neuronal damage. TRAP1 downregulation is an early and reversible event that links hypoxic stress to mitochondria ER dysfunction and cognitive impairment. Direct Trap1 overexpression or indirect upregulation via WNT5a agonism represents a promising dual therapeutic strategy for hypoxia-induced neurodegeneration and memory deficits.