Background: Traumatic brain injury (TBI) presents specific challenges for sedation management, especially in intensive care units (ICUs) in resource-limited or conflict-affected settings. Nurses play a central role in sedation; however, standardized tools such as the Richmond Agitation-Sedation Scale (RASS) are frequently underutilized. Evidence of the effectiveness of nurse-led sedation protocols in such contexts remains limited. This randomized controlled trial aimed to evaluate the influence of a nurse-led RASS-guided sedation protocol on sedation quality and care practices among patients with TBI. Methods: This study employed a randomized controlled design using block randomization and included 80 adult patients with TBI recruited from three general ICUs. Data were collected using four tools: a patient demographic and clinical data form, multiple clinical assessment scales, a pharmacological and non-pharmacological intervention checklist, and the nurse-led sedation protocol. The control group received standard sedation, whereas the intervention group underwent the RASS-guided protocol. Results: Patients in the intervention group remained within the target sedation range (−2 to +1) significantly longer (61.6% vs. 30.1%, P<0.001), showed fewer episodes of over- and undersedation, achieved superior pain control, had a lower mean Behavioral Pain Scale score (5.51 vs. 7.88, P<0.001), and received more non-pharmacological interventions with fewer sedative infusion hours (P<0.001). Conclusion The nurse-led sedation protocol enhanced sedation quality, improved pain management, and minimized sedative exposure in patients with TBI.