Background: The effectiveness and safety of COVID-19 vaccines may vary considering the contextual characteristics of middle-income countries. Thus, this study aimed to determine the effectiveness and safety of COVID-19 vaccines in middle-income countries to prevent infection, hospitalisation, Intensive Care Unit (ICU) admission, and death due to COVID-19.Methods: In this systematic review and meta-analysis we looked through Cochrane Library, MEDLINE, Embase, and LILACS databases between December 2020 and October 2021. We searched grey literature in pre-prints (MedRxiv), reference lists of articles, similar articles of relevant studies, and the WHO landscape of observational studies. We included observational studies, written in English or Spanish, conducted in middle-income countries that reported the effectiveness or safety of COVID-19 vaccines used in participants ≥16 years. Case reports/series, reviews, letters, editorials, ecological studies, animal experiments, clinical trials, and conference papers were excluded. Data were extracted from published or pre-print reports. We independently performed a random effect model metanalysis for cohort and case-control studies to assess the vaccines’ effectiveness by clinical outcomes, with a 95% confidence interval. PROSPERO registration, CRD42021274109.Findings: A total of 44 articles were included, 25 assessing safety and 19 effectiveness of vaccines. In cohort studies, full schemes showed an effectiveness of 81%(RR=0,19 95%CI: 0,09-0,43), 86%(RR=0,14 95%CI: 0,05-0,39), 87%(RR=0,13 95%CI:0,11-0,16), and 96%(RR=0,04, 95% CI: 0,01-0,22) for the outcomes of SARS-CoV-2 infection, hospitalisation, ICU admission, and death, respectively. Regarding vaccine safety, serious adverse events were detected at a very low frequency.Interpretation: Full schemes of vaccines as used in middle-income countries have high effectiveness and safety. However, there are concerns about the methodological quality of available studies. There is a need to improve the methodological quality of publications from middle-income countries and highlight the importance of contextual and cultural differences of populations to accurately evaluate vaccines in different settings.Funding: None.Declaration of Interests: We declare no competing interests.