Aim: This study aims to assess rates of antibiotic prescriptions and its determinants in in children with COVID-19 or Multisystem Inflammatory Syndrome (MIS-C). Methods: Children <18 years-old assessed in five Latin Americas countries with a diagnosis of COVID-19 or MIS-C were enrolled. Antibiotic prescriptions and factors associated with their use were assessed. Results: A total of 990 children were included: 921 (93%) with COVID-19, 69 (7.0%) with MIS-C. The prevalence of antibiotic use was 24.5% (n = 243). MIS-C with (OR = 45.48) or without (OR = 10.35) cardiac involvement, provision of intensive care (OR = 9.60), need for hospital care (OR = 6.87), pneumonia and/or ARDS detected through chest X-rays (OR = 4.40), administration of systemic corticosteroids (OR = 4.39), oxygen support, mechanical ventilation or CPAP (OR = 2.21), pyrexia (OR = 1.84), and female sex (OR = 1.50) were independently associated with increased use of antibiotics. There was significant variation in antibiotic use across the hospitals. Conclusion: Our study showed a high rate of antibiotic prescriptions in children with COVID-19, in particular in those with severe disease or MIS-C. Prospective studies are needed to provide better evidence on the recognition and management of bacterial infections in COVID-19 children.