Several studies have identified a possible association between ABO blood group and COVID-19. However, studies are of variable quality and results are inconsistent. The aim of this systematic review was to synthesize the evidence on the association between ABO and the risk of COVID-19 infection and prognosis. Searches were conducted in PubMed, MedRxive and BioRxive to identify observational studies published up to May 2021. The incidence of COVID-19 and, among the COVID-19 positive patients, the risk of hospitalization, ICU admission, mechanical ventilation and mortality were also analyzed. A total of 63 studies were included, with 6,470,438 participants. Group O was associated to a significantly lower risk of COVID-19 infection (OR O vs non-O 0.88 95%CI: 0.82–0.94; I²: 91%) and group A with a higher risk (OR A vs non-A 1.08 95%CI: 1.02–1.15). No effect of ABO on the risk of hospitalization, ICU admission or ventilation was observed. Group A was associated with higher mortality (OR A vs non-A: 1.13 95%CI 1.03–1.13), group B with lower mortality (OR B vs non-B 0.88; 95%CI 0.80–0.96), and no effect with group O was observed. The quality of the evidence was rated as “very low” and “low”. Group O would present a reduced risk of COVID-19 infection, but would not influence the prognosis of the disease. Group A would be risk factor for COVID-19 infection and mortality. Group B would not modify the risk of COVID-19 infection, but would be associated to a lower mortality risk.