Background: We systematically assessed beneficial and harmful effects of monoclonal antibodies for coronavirus disease 2019 (COVID-19) treatment, and prophylaxis in individuals exposed to severe acute respiratory syndrome coronavirus 2. Methods: We searched 5 engines and 3 registries until November 3, 2021 for randomized controlled trials evaluating monoclonal antibodies vs control in hospitalized or non-hospitalized adults with COVID-19, or as prophylaxis. Primary outcomes were all-cause mortality, COVID-19-related death, and serious adverse events; hospitalization for non-hospitalized; and development of symptomatic COVID-19 for prophylaxis. Inverse variance random effects models were used for meta-analyses. Grading of Recommendations, Assessment, Development, and Evaluations methodology was used to assess certainty of evidence. Results: Twenty-seven randomized controlled trials were included: 20 in hospitalized patients (n = 8253), 5 in non-hospitalized patients (n = 2922), and 2 in prophylaxis (n = 2680). In hospitalized patients, monoclonal antibodies slightly reduced mechanical ventilation (relative risk [RR] 0.74; 95% confidence interval [CI], 0.60-0.9; I2 = 20%, low certainty of evidence) and bacteremia (RR 0.77; 95% CI, 0.64-0.92; I2 = 7%, low certainty of evidence); evidence was very uncertain about the effect on adverse events (RR 1.31; 95% CI, 1.02-1.67; I2 = 77%, very low certainty of evidence). In non-hospitalized patients, monoclonal antibodies reduced hospitalizations (RR 0.30; 95% CI, 0.17-0.53; I2 = 0%, high certainty of evidence) and may slightly reduce serious adverse events (RR 0.47; 95% CI, 0.22-1.01; I2 = 33%, low certainty of evidence). In prophylaxis studies, monoclonal antibodies probably reduced viral load slightly (mean difference −0.8 log10; 95% CI, −1.21 to −0.39, moderate certainty of evidence). There were no effects on other outcomes. Conclusions: Monoclonal antibodies had limited effects on most of the outcomes in COVID-19 patients, and when used as prophylaxis. Additional data are needed to determine their efficacy and safety.