Complicated grief is a prolonged, bereavement-specific disorder with significant psychological and physical consequences. Although complicated grief represents a risk to individuals with substance misuse, this relationship is poorly understood. Consequently, this systematic literature review examined empirical findings regarding the relationship between substance misuse and complicated grief. We searched 11 databases to identify pertinent quantitative studies published in English. Our search yielded 12 peer-reviewed journal articles (N = 1749) published between 1997 and 2017. Included studies evaluated the prevalence, assessment, etiology, correlates, risk factors, and treatment of complicated grief and substance misuse among individuals with one or both conditions. Our review found evidence of a positive relationship between complicated grief and substance misuse. Individuals with substance misuse were at increased risk for subsequent development of complicated grief, particularly when increases in substance consumption preceded bereavement. Conversely, complicated grief predicted increases in smoking and alcohol dependence. Multiple risk factors for individuals with complicated grief and substance misuse were identified and discussed. An existing complicated grief assessment performed well among individuals with substance misuse, and grief interventions were effective in reducing symptoms of complicated grief and substance misuse simultaneously. Given the severity of consequences associated with both conditions, more research is needed to understand this relationship, identify effective assessment tools, and evaluate intervention strategies to improve outcomes.