The relative paucity of robust studies on pharmacological treatments for depression following traumatic brain injury precludes establishment of firm recommendations for its routine use in this population. The purpose of this study is to determine the efficacy and tolerability of sertraline in the treatment of post-TBI depression and improvement in quality of life. Randomized controlled trials (RCT) were identified by electronic search through PubMed, Scopus, CINAHL (Cumulative Index to Nursing and Allied Health Literature), LILACS (Literatura Latino-Americana e do Caribe em Ciencas da Saude), Cochrane Library, Clinicaltrials.gov, and HERDIN (Health Research and Development Information Network database). Random effects meta-analysis of data for depression scale scores, treatment response, and quality of life scale scores was conducted. Four RCTs were included with a total of 224 patients. There were no significant mean differences in the Hamilton Depression Rating Scale (HAM-D17) scores (MD = 2.63, 95% CI [-1.32,6.57], p = 0.19), Maier subscale scores (MD = 0.88, 95% CI [-2.26, 4.01], p = 0.58), odds ratio of treatment response (OR = 1.04, 95% CI [0.13, 8.43], p = 0.97) and quality of life scale scores (SMD = -1.52, 95% CI [-5.65, 2.61], p = 0.47) between sertraline and placebo. The pooled evidence from four RCTs shows that sertraline is not superior to placebo in terms of improving depression and quality of life of patients with post-TBI depression. There is also insufficient evidence regarding its safety in this subset of patients.