Objective: The stress response following traumatic brain injury (TBI) is a preventable cause of secondary brain injury. This can be prevented using sedation in the intensive care unit (ICU). To date, the choice of sedative agent for preventing stress response is not well-studied in literature. Methods: This prospective randomized controlled trial included 60 patients with severe TBI admitted to ICU. The patients were randomized into 2 study groups according to the choice of sedation: propofol (group I) and midazolam infusion (group II). The serum cortisol was measured as the primary outcome at admission to ICU and 48 hours following sedation infusion. The baseline Glasgow coma scale, hemodynamic, optic nerve sheath diameter (ONSD), and computed tomography scan findings were noted at admission. Glasgow outcome scale (GOS) was measured as a neurological outcome at discharge from ICU. Results: There was a statistically significant reduction in serum cortisol level in both the study groups (Δ cortisol, p-value=134.91 (50.5,208.2), 0.00 and 118.8 (42.6,160.4), 0.00, in group I and II, respectively). Serum cortisol levels were comparable among both groups at baseline and 48 hours. Similarly, there was a statistically significant difference in ONSD in both groups, but there was no difference in ONSD value between the groups at 48 hours. The GOS was also similar in both groups at discharge from ICU. Conclusion The study demonstrated a similar reduction in serum cortisol levels following 48 hours of propofol or midazolam infusion in patients with severe TBI.