Symptoms of depression are common following traumatic brain injury (TBI), impacting survivors’ ability to return to work, participate in leisure activities, and placing strain on relationships. Depression symptoms post TBI are often managed with pharmacotherapy, however, there is little research evidence to guide clinical practice. There have been a number of recent systematic reviews examining pharmacotherapy for post TBI depression. The aim of this umbrella review was to synthesize systematic reviews and meta-analyses of the effectiveness of pharmacotherapy for the management of post TBI depression in adults. Eligible reviews examined any pharmacotherapy against any comparators, for the treatment of depression in adults who had sustained TBI. Seven databases were searched, with additional searching of online journals, Research Gate, Google Scholar and the TRIP Medical Database to identify published and unpublished systematic reviews and meta-analyses in English up to May 2020. A systematic review of primary studies available between March 2018 and May 2020 was also conducted. Evidence quality was assessed using Joanna Briggs Institute Critical Appraisal Instruments. The results are presented as a narrative synthesis. Twenty-two systematic reviews were identified, of which ten reviews contained a meta-analysis. No new primary studies were identified in the systematic review. There was insufficient high quality and methodologically rigorous evidence to recommend prescribing any specific drug or drug class for post TBI depression. The findings do show, however, that depression post TBI is responsive to pharmacotherapy in at least some individuals. Recommendations for primary studies, systematic reviews and advice for prescribers is provided. Review Registration PROSPERO (CRD42020184915).