With more than 12 million emergency department visits annually related to substance abuse and mental health crises, and approximately 650,000 patients evaluated for suicide attempts, the ED is a critical clinical setting for intervention. This review presents an ED-focused approach to assessing depression and suicide risk, including background information on the classification, epidemiology, and known pathology of depression, as well as the assessment of suicide risk within depression. Best-practice recommendations are made regarding current mental status evaluation and management strategies. Cutting-edge interventions and approaches, including the use of assessment and screening tools, implementation of safety planning, the Zero Suicide model, continuing postdischarge contact, lethal-means counseling, and novel pharmacotherapy approaches are also reviewed.