Background <p>Neurosurgical patients are at an increased risk of developing agitation and intensive care unit (ICU) delirium due to direct inflammation and oxidative stress associated with neurosurgery. There are limited therapeutic options for the management of agitation and delirium in this population; and neurosurgical patients have been largely underrepresented in previous studies. This study aimed to assess the impact of valproic acid (VPA) on adjunctive agent requirements for the management of agitation in neurosurgical ICU patients.</p> Methods <p>This was a single-center, retrospective, descriptive study evaluating adult neurosurgical patients admitted between 1 April 2016 and 31 August 2023. Patients were included if they were on VPA for at least 3&#xa0;days for the treatment of agitation. The primary outcome evaluated changes in total daily doses (TDD) of adjunctive sedative agent requirements following VPA initiation. Secondary outcomes included the incidence of positive Richmond Agitation and Sedation Scale (RASS) scores and liberation from physical restraints. Safety outcomes included the occurrence of thrombocytopenia, hyperammonemia, and liver function test (LFT) abnormalities while on VPA.</p> Results <p>A total of 91 patients were included in the analysis. Significant reductions in TDD of opioids (<i>p</i> = 0.001), benzodiazepines (<i>p</i> = 0.003), and dexmedetomidine (<i>p</i> &lt; 0.001) were seen on day 3 of VPA therapy. Significant reductions in the number of patients with positive RASS scores (<i>p</i> = 0.001) and the number of patients requiring physical restraints (<i>p</i> = 0.001) were also observed from day 1 to day 3 of VPA therapy.</p> Conclusions <p>Initiation of VPA was associated with a significant decrease in adjunctive sedative agent requirements, positive RASS scores, and number of patients requiring physical restraints. Further prospective studies are needed to determine the optimal role of VPA for the management of agitation in neurosurgical ICU patients.</p>