Hypoxia in water that caused by reduced levels of oxygen occurred frequently, due to the complex aquatic environment. Hypoxia tolerance for fish depends on a complete set of coping mechanisms such as oxygen perception and gene-protein interaction regulation. The present study examined the short-term effects of hypoxia on the brain in Takifugu rubripes. We sequenced the transcriptomes of the brain in T. rubripes to study their response mechanism to acute hypoxia. A total of 167 genes were differentially expressed in the brain of T. rubripes after exposed to acute hypoxia. Gene ontology and KEGG enrichment analysis indicated that hypoxia could cause metabolic and neurological changes, showing the clues of their adaptation to 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.