Background Individuals who are homeless or vulnerably housed are at an increased risk for mental illness, other morbidities and premature death. Standard case management interventions as well as more intensive models with practitioner support, such as assertive community treatment, critical time interventions, and intensive case management, may improve healthcare navigation and outcomes. However, the definitions of these models as well as the fidelity and adaptations in real world interventions are highly variable. We conducted a systematic review to examine the effectiveness and cost-effectiveness of case management interventions on health and social outcomes for homeless populations. Methods and findings We searched Medline, Embase and 7 other electronic databases for trials on case management or care coordination, from the inception of these databases to July 2019. We sought outcomes on housing stability, mental health, quality of life, substance use, hospitalization, income and employment, and cost-effectiveness. We calculated pooled random effects estimates and assessed the certainty of the evidence using the GRADE approach. Our search identified 13,811 citations; and 56 primary studies met our full inclusion criteria. Standard case management had both limited and short-term effects on substance use and housing outcomes and showed potential to increase hostility and depression. Intensive case