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Abstract Background COVID-19 has caused millions of deaths globally, with vulnerable populations such as people experiencing homelessness (PEH) at higher risk. This systematic review and meta-analysis aims to identify the prevalence and key factors contributing to vaccine acceptance experienced by PEH. Methods The protocol of this study was registered in PROSPERO (CRD42023391659). We included studies that reported relevant information about vaccine acceptance or vaccine hesitant/refusal among PEH. Eight databases were systematically searched in January 2023. Meta-analysis was conducted for the prevalence of vaccine acceptance, vaccine uptake, and factors associated with vaccine acceptance. Attitudes toward vaccines were combined into bar charts. Result A total of 29 papers were included in this systematic review and 19 papers were included for meta-analysis. The pooled prevalence of COVID-19 vaccine acceptance among PEH was 66% (95%CI: 58%-73%). Our meta-regression showed vaccine acceptance was significantly increased over time. Moreover, subgroup meta-analysis showed that PEH were more likely to accept the COVID-19 vaccine after June 2021 (78%, 95%CI: 65%-86%) compared with earlier period (56%, 95%CI: 54%-59%). Subgroup meta-analysis also revealed that women and participants without underlying medical condition (chronic diseases) were significantly less likely to accept the COVID-19 vaccine, compared to men and those with medical conditions, respectively. Conclusion The study emphasizes the need for targeted public health interventions aimed at increasing vaccine acceptance among PEH, especially at the early stage of the pandemic, among females, those without underlying medical conditions, being Black (in Canada and the USA), and young people. These interventions should address the common concerns of vaccine safety, adverse effects, effectiveness, and distrust in health care systems. In addition to offering vaccinations in different areas convenient to them, education programs could be established to increase vaccine acceptance among PEH.