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Background Although COVID-19 is usually mild in children, antibiotics are frequently prescribed during hospitalisation, often without evidence of bacterial infection.Objective To assess the frequency and predictors of antibiotic use in children hospitalised with SARS-CoV-2 infection in Switzerland.Methods In this nationwide prospective study, children aged 0–18 years hospitalised with confirmed SARS-CoV-2 infection or symptoms compatible with paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) between January 2022 and March 2023 were included. Univariable and multivariable logistic regression analyses were used to identify risk and protective factors for antibiotic use. A sensitivity analysis was conducted excluding high-risk patients.Results Among 1944 hospitalised children, 586 (30%) received antibiotics. Of these, 71 (12%) had a clinically suspected bacterial infection without microbiological confirmation and 41 (7%) had microbiologically confirmed infection. Predictors of antibiotic use were microbiologically confirmed bacterial infection (aOR 138.08), clinically suspected bacterial infection (aOR 114.48), haematologic/oncologic disease (aOR 6.77), PIMS-TS (aOR 5.36), fever (aOR 2.98), neonatal age (aOR 2.80) and treatment in tertiary centres (aOR 1.65). After excluding high-risk patients, however, treatment in tertiary centres and PIMS-TS were no longer significant predictors in the sensitivity analysis. Respiratory distress/tachypnoea (aOR 0.72) and admission with confirmed SARS-CoV-2 as the primary diagnosis (aOR 0.42) were associated with lower antibiotic use in the primary analysis. After excluding high-risk patients, this association was no longer observed and nasal symptoms (aOR 0.68) and seizures (aOR 0.34) emerged as protective factors.Conclusion Antibiotics were frequently prescribed to children hospitalised with SARS-CoV-2 despite limited evidence of bacterial infection. Our findings underscore the need to strengthen antimicrobial stewardship in paediatric COVID-19 care.