Background: Several studies have examined the possible role of beta-blockers, including esmolol, in controlling intracranial pressure (ICP). This study aimed to evaluate the effect of esmolol on ICP in patients with severe traumatic brain injury. Methods: In this case-control study, all TBI patients with ICP > 20 cmH2O, who were admitted to ICU during the study period, were included. Some patients received standard treatment plus esmolol (500 μg/kg and then 50 mg/kg/min for 24 hours), and some others just received standard treatment with no esmolol. The patients were monitored, and the ICP measurement was performed via inserted intra-ventricular catheter. The ICP and vital signs were measured and recorded before, 8, 16, and 24 hours after starting the treatment in the two groups, and the findings were then compared. Results: Twenty-two patients (13 males and 9 females) were included in this study, of whom 12 patients received esmolol, and 10 patients were in the control group. The mean age of those who received esmolol was smaller than those who did not receive it (46.6 ± 18.5 vs. 62.3 ± 19.1 years; P = 0.08). Moreover, the mean length of the ICU stay was smaller in the esmolol receivers than the control group (5.6 ± 1.1 vs. 17.3 ± 7.7 days; P = 0.04 (there was no significant difference between the two groups in terms of mortality rates (P = 0.30). The variations of the vital signs over time was not significantly different between the two groups (P > 0.05); however, the mean of ICP was lower in those who received esmolol compared to the control group at all checkpoints (P < 0.05). Conclusions: Those patients with TBI who received esmolol as part of their ICP control management in ICU had lower ICP than those who received no esmolol.