IntroductionThe cognitive dysfunction associated with nitrous oxide abuse is gradually becoming a major global public health concern. Despite the increasing prevalence of nitrous oxide abuse, there are currently no authorised/approved treatment options. Hyperbaric oxygen therapy (HBOT) has been proven to be an efficient method to improve cognitive function. The current randomised, double-blinded, placebo-controlled trial will explore the effect of HBOT on cognitive dysfunction induced by nitrous oxide abuse.Methods and analysisEighty participants who abuse nitrous oxide and have cognitive dysfunction, including memory decline, disorientation, attention deficits, slower reactions and learning disabilities, will be included in the trial. They will be randomly assigned to receive either HBOT or sham-HBOT 90–120 min once daily for 5 days per week for 2 weeks. The primary outcome will be the improvement in the total score of the MATRICS Consensus Cognitive Battery, which will measure comprehensive cognitive function between the two groups. Additionally, attention will be measured by integrated visual and auditory continuous performance tests, executive function will be measured by the Wisconsin card sorting test, intelligence will be measured by Raven’s standard progressive matrices and cognitive control will be measured by the Stroop colour word interference test.Ethics and disseminationThis protocol was approved by the West China Hospital of Sichuan University Biomedical Research Ethics Committee. The report of the study will be disseminated via scientific forums including peer-reviewed publications and presentations at national and international conferences.Trial registration numberChinese Clinical Trial Registry (ChiCTR2100047111).