Post-stroke depression (PSD) is common, affecting approximately one third of stroke survivors at any one time after stroke. Individuals with PSD are at a higher risk for suboptimal recovery, recurrent vascular events, poor quality of life, and mortality. Although PSD is prevalent, uncertainty remains regarding predisposing risk factors and optimal strategies for prevention and treatment. This is the first scientific statement from the American Heart Association on the topic of PSD. This multispecialty statement provides a comprehensive review of the current evidence and gaps in current knowledge of the epidemiology, pathophysiology, outcomes, management, and prevention of PSD, and provides implications for clinical practice.