Background Nitrous oxide (N2O), also called “laughing gas,” is the most commonly used inhalation anesthetic in dentistry. The N2O is no longer used, because of the long-term neurologic and cardiovascular sequelae. Due to its sedative and euphoric properties, N2O is often used for recreational use or in some erotic activities. Accidental deaths are mainly associated with the uses of N2O: death can occur from sudden cardiac arrhythmia or, most commonly, acute asphyxiation due to hypoxia. This paper aims to study the literature concerning deaths due to N2O intoxication and highlight pathological findings useful for diagnosis when the crime scene investigation does not reveal any evidence. Materials and methods The authors conducted the literature search by PubMed and Scopus databases, searching for articles from 1 January 1970 to 1 March 2020 using the key terms: “Nitrous oxide,” “Laughing gas,” “Hypoxic damage,” “Nitrous oxide anesthesia,” and “Nitrous oxide death.” Results and discussion A total of 244 articles were collected. Only 26 articles were included in the systematic review. Most of the deaths from intoxication are due to asphyxiation; the diagnosis is often difficult and immunohistochemistry could be helpful. Nitrous oxide increases the intracellular adhesion molecule expression, E- and P-Selectin (markers of the early inflammatory response), and HIF-1 α (indicative of oxidative stress during ischemia-reperfusion). Conclusion The macroscopic and microscopic signs of N2O intoxication are non-specific, but N2O has been proven to cause hypoxic damage to the brain. The suspicion of the presence of the gas in the environment should guide the pathologist. Tissue analyzes provide important information; immunohistochemical stains can confirm hypoxic damage through the use of markers such as HIF-1 α, E-Selectin, and P-Selectin.