COVID-19 self-testing strategy (COVIDST) can rapidly identify symptomatic and asymptomatic SARS-CoV-2-infected individuals and their contacts, potentially reducing transmission. In this living systematic review, we evaluated the evidence for real-world COVIDST performance. Two independent reviewers searched six databases (PubMed, Embase, Web of Science, World Health Organization database, Cochrane COVID-19 registry, Europe PMC) for the period April 1st, 2020, to January 18th, 2023. Data on studies evaluating COVIDST against laboratory-based conventional testing and reported on diagnostic accuracy, feasibility, acceptability, impact, and qualitative outcomes were abstracted. Bivariate random effects meta-analyses of COVIDST accuracy were performed (n = 14). Subgroup analyses (by sampling site, symptomatic/asymptomatic infection, supervised/unsupervised strategy, with/without digital supports) were conducted. Data from 70 included studies, conducted across 25 countries with a median sample size of 817 (range: 28–784,707) were pooled. Specificity and DOR was high overall, irrespective of subgroups (98.37–99.71%). Highest sensitivities were reported for: a) symptomatic individuals (73.91%, 95%CI: 68.41–78.75%; n = 9), b) mid-turbinate nasal samples (77.79%, 95%CI: 56.03–90.59%; n = 14), c) supervised strategy (86.67%, 95%CI: 59.64–96.62%; n = 13), and d) use of digital interventions (70.15%, 95%CI: 50.18–84.63%; n = 14). Lower sensitivity was attributed to absence of symptoms, errors in test conduct and absence of supervision or a digital support. We found no difference in COVIDST sensitivity between delta and omicron pre-dominant period. Digital supports increased confidence in COVIDST reporting and interpretation (n = 16). Overall acceptability was 91.0–98.7% (n = 2) with lower acceptability reported for daily self-testing (39.5–51.1%). Overall feasibility was 69.0–100.0% (n = 5) with lower feasibility (35.9–64.6%) for serial self-testing. COVIDST decreased closures in school, workplace, and social events (n = 4). COVIDST is an effective rapid screening strategy for home-, workplace- or school-based screening, for symptomatic persons, and for preventing transmission during outbreaks. These data will guide COVIDST policy. Our review demonstrates that COVIDST has paved the way for self-testing in pandemics worldwide.