BACKGROUND: This study aims to investigate the effects of aerobic exercise training on learning and memory (L&M) performance in rats exposed to altitude hypoxia and its relationship with hippocampal plasticity and the PKA-CREB-BDNF signaling pathway. METHODS: Male Sprague-Dawley rats were exposed to 14.2% hypoxia with or without 60 min of non-weight-bearing swimming training for 8 weeks. The L&M performance was evaluated using the Morris water maze, and the mRNA expression of PSD95, SYP, PKA, CREB, CBP, and BDNF in the hippocampus was detected. RESULTS: Chronic hypoxia exposure significantly impaired L&M performance and reduced the mRNA expression of hippocampal PSD95, SYP, PKA, CREB, CBP, and BDNF. Aerobic exercise training effectively reversed these changes by enhancing hippocampal synaptic plasticity through the activation of the PKA-CREB-BDNF signaling pathway. CONCLUSION: Aerobic exercise training can alleviate the decline in L&M performance caused by altitude hypoxia exposure, possibly through the activation of the hippocampal PKA-CREB-BDNF signaling pathway.