Sympathetic activation, manifesting as tachycardia and hypertension, is a known occurrence following direct laryngoscopy and endotracheal intubation. Although considered transient and benign in most patients, the marked hemodynamic changes can precipitate perioperative cardiac events in patients with preexisting cardiac risk factors. Perioperative cardiac events are associated with increased morbidity and mortality, prolonged hospitalizations, and increased hospital costs. A multitude of pharmacologic agents have been employed to mitigate the tachycardia and hypertension associated with airway manipulation. Fentanyl is the adjuvant agent most commonly administered to facilitate induction of anesthesia and subsequent airway manipulation. Dexmedetomidine, another adjuvant, has demonstrated effectiveness in suppressing the hemodynamic response to intubation as well as potentially reducing perioperative ischemic events. The purpose of this systematic review was to compare the effectiveness of dexmedetomidine to fentanyl for attenuating the sympathetic response to direct laryngoscopy and endotracheal intubation. Literature and pertinent randomized control trials were searched for inclusion within this review. Four trials were included in this systematic review using the PRISMA checklist. Data was collected from each study and critically appraised using the CASP tool, and a cross analysis was then performed. This systematic review found dexmedetomidine to be superior to fentanyl in attenuating the hemodynamic response to airway manipulation. However, further research is necessary to better determine the effectiveness of these medications on patients with preexisting cardiovascular disease.