In this systematic review, we investigated research literature evaluating the effectiveness of occupational therapy interventions focusing on participation and performance in occupations related to paid and unpaid employment and education for people with serious mental illness. The review included occupation- and activity-based interventions and interventions addressing performance skills, aspects of the environment, activity demands, and client factors. The results indicate that strong evidence exists for the effectiveness of supported employment using individual placement and support to result in competitive employment. These outcomes are stronger when combined with cognitive or social skills training. Supported education programs emphasizing goal setting, skill development, and cognitive training result in increased participation in educational pursuits. The evidence for instrumental activities of daily living interventions that targeted specific homemaking occupations and supported parenting was limited but positive. Environmental cognitive supports, such as signs, and other compensatory strategies are useful in managing maladaptive behavior.