N2O, or laughing gas, is generally used for anesthesia, especially in stomatology and pediatrics but is also commonly used recreationally. Cognitive dysfunction induced by the recreational use of N2O is rare. Here, we present the case of an 18-year-old female with a history of having used N2O recreationally for 5 months who suffered from encephalatrophy and severe cognitive dysfunction. All of the symptoms gradually subsided with ~20 days of treatment by hyperbaric oxygenation. We hypothesize that the long-term use of N2O may have induced a chronic state of systemic hypoxia that further induced cerebral atrophy with impaired cognitive function. Hyperbaric oxygen therapy (HBOT) is reported here for the first time as an important therapeutic element for treating N2O toxicity due to recreational use.