Background Homelessness has emerged as a public health priority, with growing numbers of vulnerable populations despite advances in social welfare. In February 2020, the United Nations passed a historic resolution, identifying the need to adopt social‐protection systems and ensure access to safe and affordable housing for all. The establishment of housing stability is a critical outcome that intersects with other social inequities. Prior research has shown that in comparison to the general population, people experiencing homelessness have higher rates of infectious diseases, chronic illnesses, and mental‐health disorders, along with disproportionately poorer outcomes. Hence, there is an urgent need to identify effective interventions to improve the lives of people living with homelessness. Objectives The objective of this systematic review is to identify, appraise, and synthesise the best available evidence on the benefits and cost‐effectiveness of interventions to improve the health and social outcomes of people experiencing homelessness. Search Methods In consultation with an information scientist, we searched nine bibliographic databases, including Medline, EMBASE, and Cochrane CENTRAL, from database inception to February 10, 2020 using keywords and MeSH terms. We conducted a focused grey literature search and consulted experts for additional studies. Selection Criteria Teams of two reviewers independently screened studies against our inclusion criteria. We included randomised control trials (RCTs) and quasi‐experimental studies conducted among populations experiencing homelessness in high‐income countries. Eligible interventions included permanent supportive housing (PSH), income assistance, standard case management (SCM), peer support, mental health interventions such as assertive community treatment (ACT), intensive case management (ICM), critical time intervention (CTI) and injectable antipsychotics, and substance‐use interventions, including supervised consumption facilities (SCFs), managed alcohol programmes and opioid agonist therapy. Outcomes of interest were housing stability, mental health, quality of life, substance use, hospitalisations, employment and income. Data Collection and Analysis Teams of two reviewers extracted data in duplicate and independently. We assessed risk of bias using the Cochrane Risk of Bias tool. We performed our statistical analyses using RevMan 5.3. For dichotomous data, we used odds ratios and risk ratios with 95% confidence intervals. For continuous data, we used the mean difference (MD) with a 95% CI if the outcomes were measured in the same way between trials. We used the standardised mean difference with a 95% CI to combine trials that measured the same outcome but used different methods of measurement. Whenever possible, we pooled effect estimates using a random‐effects model. Main Results The search resulted in 15,889 citations. We included 86 studies (128 citations) that examined the effectiveness and/or cost‐effectiveness of interventions for people with lived experience of homelessness. Studies were conducted in the United States (73), Canada (8), United Kingdom (2), the Netherlands (2) and Australia (1). The studies were of low to moderate certainty, with several concerns regarding the risk of bias. PSH was found to have significant benefits on housing stability as compared to usual care. These benefits impacted both high‐and moderate‐needs populations with significant cimorbid mental illness and substance‐use disorders. PSH may also reduce emergency department visits and days spent hospitalised. Most studies found no significant …