Neuroleptic malignant syndrome (NMS) is a life-threatening condition occurring rarely when patients are exposed to neuroleptic drugs in clinical practice. It can occur in both genders with similar frequency. It is manifested by autonomic dysfunction, muscle rigidity, blood pressure fluctuation, fever, altered mental status, electrolyte imbalance, and organ dysfunction in the form of renal failure. Presentation can vary from mild to severe conditions in which multiorgan dysfunction can occur. Even permanent neurological damage can persist. Early detection and treatment may prevent complications in these patients with NMS. Always one needs to be highly suspicious when a patient is on neuroleptic drugs and develops any of the symptoms suspicious of NMS. We have presented a case series of three patients, presenting in three different clinical scenarios, who had developed NMS. NMS symptoms were detected earlier in all the cases and were treated successfully. This systematic review along with the case series will definitely enhance the knowledge regarding this rare but important clinical condition among emergency care physicians and improve the outcome of patients presenting with this condition. Objective: Increase the knowledge of NMS among critical care physicians to aid in early diagnosis and prevention of complications. Additionally, review various approaches to treating this condition. Materials and methods: We are sharing our clinical experience with NMS. This critical entity is extensively reviewed in this systematic review article, along with three important clinical cases presenting with NMS, to extend knowledge regarding this important entity to emergency care clinicians. More than 100 case series, case reports, and review articles in the available literature were studied while writing this systematic review.