Background Paroxysmal sympathetic hyperactivity, which affects up to 10% of all acquired brain injury survivors, is characterized by elevated heart rate, blood pressure, respiratory rate, and temperature; diaphoresis; and increased posturing. Pharmacological agents that have been studied in the management of this disorder include opiates, γ-aminobutyric acid agents, dopaminergic agents, and β blockers. Although paroxysmal sympathetic hyperactivity is a relatively common complication after acquired brain injury, there is a paucity of recommendations or comparisons of agents for the management of this disorder. Objective To evaluate all relevant literature on pharmacological therapies used to manage patients with paroxysmal sympathetic hyperactivity to help elucidate possible best practices. Methods Of the 27 studies evaluated for inclusion, 10 studies received full review: 4 retrospective cohort studies, 5 single case studies, and 1 case series. Results Monotherapy is usually not effective in the management of paroxysmal sympathetic hyperactivity and multiple agents with different mechanisms of action should be considered. α2-Agonists such as dexmedetomidine may hold some slight clinical efficacy over agents like propofol, and with respect to oral medications, propranolol might convey some slight advantage compared to others. However, with the limited data available, these results must be interpreted with caution. Conclusions As the treatment of paroxysmal sympathetic hyperactivity is reactive to symptomatic evolution over time, critical care nurses play a vital role in the monitoring and treatment of these patients. Limited data exist on the management of paroxysmal sympathetic hyperactivity and larger robust data sets are needed to guide decision-making. (Critical Care Nurse. 2020;40[3]:e9-e16)