Abstract Hypoxia is reduced levels of oxygen. Especially in water, due to the complex environment, hypoxic situations often occur. Although fish can survive in low-oxygen waters, this survival ability depends on a complete set of coping mechanisms such as oxygen perception and gene-protein interaction regulation. The research on this mechanism is very meaningful. The present study was undertaken to examine the short-term effects of hypoxia on the brain in Takifugu rubripes. We sequenced the transcriptomes of the brain in T. rubripes to studied their response mechanism to acute hypoxia. Total 167 genes with adjusted P values<0.05 were differentially expressed in the brain of T. rubripes exposed to acute hypoxia. However, hif1a, the master transcriptional regulator of the adaptive response to hypoxia, was not significantly regulated, which indicated that the T. rubripes brain might prevent the HIF-1 signaling pathway. Then Gene Ontology and KEGG Enrichment Analysis were carried out. The results indicated that hypoxia could cause metabolic and neurological changes, showing the clues of their adaptation to acute hypoxia. Overall, the sequenced transcriptomes of the brain in T. rubripes showed small changes under acute hypoxia. As the most complex and important organ, the brain of T. rubripes might be able to create a self-protection mechanism to resist or reduce damage caused by acute hypoxia stress.