Homelessness prevention for single adults at risk of or experiencing multiple exclusion homelessness (MEH) has received limited attention in research. This systematic review focused on the effectiveness of primary, secondary, and tertiary homelessness prevention interventions and strategies for this population. We searched four databases (Embasse, PsycInfo, Medline, and Allied Social Sciences Index and Abstracts [ASSIA]) for peer-reviewed empirically completed quantitative and qualitative studies and systematic reviews between 1992 and 2021. We identified ten categories of interventions based on the kind of support they provide: accommodation, financial assistance, case management, outreach, mental health care, joint mental health and substance use care, substance use care, other social support, policies and legal assistance. We found that research has principally focused on tertiary prevention, the prevention of chronic homelessness, and there is a lack of research on the effectiveness of upstream primary prevention strategies that would intervene before someone is at imminent risk of homelessness. However, within the secondary and tertiary prevention space, the best approach was a multifaceted cross-sector collaboration of different services. Many studies concluded that those at risk of or experiencing MEH require high intensity services combining a range of housing and support service options. Housing First, Assertive Community Treatment, Critical Time Intervention were high intensity services that were consistently found to be effective in preventing homelessness. Intensive case management had mixed evidence on effectiveness. Financial assistance was identified as important for preventing first-time, recurrent, and chronic homelessness in many studies and may be essential, but unlikely to be enough on its own. Finally, the prevention of homelessness after discharge from institutional care was found to be critical with several interventions showing to be effective here.