To explore the mechanism of Angelica polysaccharide in improving cognitive impairment caused by hypoxia at high altitudes through network pharmacology and experimental validation. Similarity ensemble approach (SEA)was used to predict the target of each monosaccharide of Angelica polysaccharide and obtained the target related to cognitive impairment caused by hypoxia at high altitudes using GeneCards and other databases. The intersection of these targets was analyzed, leading to the construction of a Protein-Protein Interaction( PPI) network and subsequent Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. A total of 303 targets for Angelica polysaccharides and 783 targets for hypoxia-induced cognitive impairment were identified, with 29 common targets. Enrichment analysis indicated that Angelica polysaccharides might exert their effects by modulating signaling pathways such as PI3K/Akt, JAK-STAT, and HIF-1. In a Morris water maze experiment with mice, results showed that Angelica polysaccharides shortened the latency period, increased the number of platform crossings, and reduced the levels of malondialdehyde (MDA) and acetylcholinesterase (AchE) in mice hippocampal and cortical tissues, while increasing superoxide dismutase (SOD) levels and decreasing inflammatory factor levels. Additionally, Angelica polysaccharides upregulated the expression of PI3K, P-Akt, Akt, and Bcl-2 and downregulated Bax protein expression in the hippocampus and cortex of mice, improving pathological damage in the hippocampal tissue of mice. Angelica polysaccharide could improve the cognitive impairment caused by hypoxia at high altitudes, likely associated with their antioxidant, anti-inflammatory and regulation of PI3K-Akt signaling pathway.