Background <p>Most of the sedative and analgesic drugs used in patients with head injury cause a dose-dependent decrease in blood pressure, which may further worsen secondary neurologic injury. The sympathomimetic profile of ketamine, along with its neuroprotectant effect, can have a beneficial effect in these patients.</p> Methods <p>A total of 60 adult patients with severe traumatic brain injury were randomized to receive either ketamine infusion at 3&#xa0;mg/kg/h or normal saline. The study drugs were given by infusion while intracranial pressure (ICP) monitoring was going on. Systemic hemodynamics, arterial blood gas values, ICP, cerebral perfusion pressure (CPP), and jugular venous oxygen saturation were monitored. At the end of&#xa0;3&#xa0;months, neurological outcome was recorded by an independent observer using the Glasgow Outcome Scale-Extended.</p> Results <p>Baseline values of hemodynamic parameters were comparable in the two groups. In the initial 4–6&#xa0;h, patients in the ketamine group had a significantly higher level of blood pressure and CPP than patients in the control group, but the effect was not sustained after 6&#xa0;h. Similarly, a significant reduction in ICP was observed only for a brief period, between the fourth and sixth hours. Vasopressors were more often used in the control group (13 [43.3%] vs. 5 [16.6%]; <i>p</i> = 0.02). There was no difference in the neurological outcome at 3&#xa0;months in both groups.</p> Conclusions <p>There was no significant improvement in neurological outcome with ketamine infusion in patients with severe traumatic brain injury. There was a trend toward better CPP and lower ICP; however, the difference was statistically insignificant.</p> <p>Trial registered at Central Trial Registry of India (CTRI/2018/09/015729) at <a href="https://ctri.nic.in/Clinicaltrials/">https://ctri.nic.in/Clinicaltrials/</a></p>