Abstract Background Severe acute respiratory syndrome coronavirus 2 continues to spread around the world, particularly in sub-Saharan Africa. However, outside South Africa, as in adults, the pandemic has had very little impact on African children and adolescents, despite very low vaccination coverage. In addition, cases of multisystemic inflammatory syndrome in children were anecdotal in sub-Saharan Africa. Aims To identify plausible hypotheses that may explain the low prevalence and mortality of Covid-19 in children in sub-Saharan Africa. Methods A narrative review of the literature Results We have identified five major hypotheses that may explain the low prevalence and mortality of COVID-19 in children and adolescents in sub-Saharan Africa: 1) the lack of a proper epidemiological study; 2) the youthfulness of the population in sub-Saharan Africa, for a disease that essentially concerns elderly subjects with comorbidities; 3) immunomodulation due to frequent contact with certain infectious agents and/or vaccines, 4) cross-reactive immunity between SARS-CoV-2 and different strains of human coronaviruses of different lineage, and 5) the widespread and off-label use of antimalarials and other drugs such as zinc, vitamin C and other complementary therapies. Conclusion All these hypotheses deserve to be confirmed in these populations by specific studies with a rigorous design. Ethics None declared.