Today, the concomitant abuse of nitrous oxide (N2O) and illicit drugs is evident and problematic. However, there are few reports regarding the clinical manifestations of N2O users when they present to the emergency department (ED). The purpose of this study was to describe the clinical presentations, the associated illicit substances used in combination, and the outcomes in N2O users visiting the ED. This was a retrospective observational cohort study. All N2O adult users admitted to the ED at Linkou Chang Gung Memorial Hospital between 2012 and 2020 were included. Demographic variables, clinical symptoms, and examination results were collected from medical records. Univariate comparisons were conducted between pure N2O users and combined illicit drug users. A total of 40 patients were included, 24 of which were pure N2O users. Limb weakness and numbness accounted for the majority of chief complaints. Neurologic symptoms were the most common clinical manifestations (90%). A more severe ED triage level, faster heart rate, greater agitation, and cardiovascular symptoms were significantly noted in combined illicit drug users. In ED, limb numbness/weakness should arouse physicians’ awareness of patients using N2O. Combined use of N2O and illicit drugs can cause great harm to health.