BACKGROUND: Traumatic brain injury (TBI) is a common presentation in emergency departments worldwide. Approximately 1.4 million adults present with TBI in England and Wales annually. Post-TBI depression (PTD) is a common neuropsychiatric consequence, affecting up to 50% of patients within two years, and is associated with adverse functional outcomes. PTD remains underdiagnosed and undertreated. Sertraline, a selective serotonin reuptake inhibitor (SSRI), has shown potential in reducing PTD incidence, yet evidence of its effectiveness in preventing depression from adequately powered trials is lacking. This randomised controlled trial aims to compare the clinical and cost-effectiveness of sertraline in reducing the risk of PTD in adults compared to usual care. METHODS: The design is a multi-centre, double-blind, placebo-controlled, randomised controlled trial (RCT) aiming to recruit 514 participants. Eligible adults (aged ≥ 18 years) with possible, mild or moderate-severe TBI within eight weeks of injury and without current major depressive disorder (MDD) are randomly assigned to receive sertraline (100 mg daily) or placebo for 12 months. The primary outcome is depressive symptom severity at 12 months, measured using the Patient Health Questionnaire-9. Secondary outcomes include incidence rates of major depressive disorder, psychiatric comorbidities, cognitive impairment, substance use, carer burden, productivity and cost-effectiveness at 6, 12 and 18 months. DISCUSSION: This is the first adequately powered RCT to investigate sertraline as a preventive intervention for PTD. Findings will help inform whether prescribing an SSRI soon after a TBI may reduce the risk of depression and improve functional outcomes. TRIAL REGISTRATION: This study is registered in the European Union Drug Regulating Authorities Clinical Trials Database (EudraCT no. 2022-000072-18, date: 7 January 2022) and the ISRCTN - The UK's Clinical Study Registry (ISRCTN no. 17518945, date: 23 December 2022, https://www.isrctn.com/ISRCTN17518945 ).