Introduction Anti‐N‐methyl‐D‐aspartate receptor encephalitis is caused by auto‐antibodies that target the N‐methyl‐D‐aspartate receptor. Autonomic instability is a hallmark of the disease. The objective of this case series is to examine how anesthesia affects pediatric patients with this disease. Methods We performed a retrospective chart review of 28 records in 17 patients who underwent anesthesia. Our primary outcomes were hemodynamic changes during the perioperative period. Heart rate, systolic and diastolic blood pressures, respiratory rate, and oxygen saturation comprise our endpoints. A subgroup of patients, who underwent imaging with anesthesia, was then compared to controls. Results In anti‐N‐methyl‐D‐aspartate receptor encephalitis cases, there were significant percent changes from baseline in heart rate; median = −14.3%, 95% CI (−19.3, −9.0), p < .01 at 30 min and −15.7%, (−21.1, −9.8), p < .01 at 60 min; in systolic blood pressure, −19.4%, (−23.7, −14.8) at 30 min, p < .01, and −14.8%, (−19.7, −9.5) at 60 min, p < .01; in diastolic blood pressure, −41.9%, (−46.9, −36.3), p < .01 at 30 min, and −37.5%, (−43.4, −30.9), p < .01 at 60 min. When compared to controls, there were no significant differences between the two groups across time of anesthesia (baseline to 60 min) in heart rate (p = .24), systolic blood pressure (p = .30), and diastolic blood pressure (p = .11). No patients experienced hemodynamic lability under anesthesia. One patient, with severe symptoms, died within 24 h of anesthesia. Conclusion Although pediatric patients with anti‐N‐methyl‐D‐aspartate receptor encephalitis experienced vital sign changes with anesthesia, they were not clinically significant and they behaved similarly to controls. Disease severity may be a risk factor for perioperative complications.