Background: Traumatic brain injury (TBI) is a major health problem worldwide. Secondary injuries after TBI, including diffuse axonal injury (DAI) often occur, and proper treatments are needed in this regard. It has been shown that glibenclamide could reduce secondary brain damage after experimental TBI and improve outcomes. Objectives: We aim to evaluate the role of glibenclamide on the short-term outcome of patients with DAI due to moderate to severe TBI. Patients and Methods: In this controlled randomized clinical trial, 40 patients withmoderate to severe TBI were assigned to glibenclamide (n = 20) and control (n = 20) groups. Six hours after admission the intervention group received 1.25 mg glibenclamide every 12 hours. The Glasgow coma scale (GCS) was administered at admission, in the first 24 and 48 hours, at one week post-trauma and at discharge. The Glasgow outcome scale (GOS) was also administered at discharge. All results were evaluated and compared between groups. Results: Patients treated with glibenclamide compared to the control group had a significantly better GCS score one week posttrauma (P = 0.003) and at discharge (P = 0.004), as well as a better GOS score at discharge (P = 0.001). The glibenclamide group also had a shorter length of hospital stay compared to the control group (P = 0.03). In the control group, two patients (10%) died during the first week post-trauma, but there was no mortality in the glibenclamide group (P = 0.48). Conclusions: Treatment with glibenclamide in patients with DAI due to moderate to severe TBI significantly improves short-term outcomes.