Depression is one of the most common conditions to emerge after traumatic brain injury (TBI), and despite its potentially serious consequences it remains undertreated. Treatment for post-traumatic depression (PTD) is complicated due to the multifactorial etiology of PTD, ranging from biological pathways to psychosocial adjustment. Identifying the unique, personalized factors contributing to the development of PTD could improve long-term treatment and management for individuals with TBI. The purpose of this narrative literature review was to summarize the prevalence and impact of PTD among those with moderate to severe TBI and to discuss current challenges in its management. Overall, PTD has an estimated point prevalence of 30%, with 50% of individuals with moderate to severe TBI experiencing an episode of PTD in the first year after injury alone. PTD has significant implications for health, leading to more hospitalizations and greater caregiver burden, for participation, reducing rates of return to work and affecting social relationships, and for quality of life. PTD may develop directly or indirectly as a result of biological changes after injury, most notably post-injury inflammation, or through psychological and psychosocial factors, including pre injury personal characteristics and postinjury adjustment to disability. Current evidence for effective treatments is limited, although the strongest evidence supports antidepressants and cognitive behavioral interventions. More personalized approaches to treatment and further research into unique therapy combinations may improve the management of PTD and improve the health, functioning, and quality of life for individuals with TBI.