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Background Antibiotics are widely used to manage acute asthma exacerbations, despite little evidence for their effectiveness. This study assesses the added value of antibiotics alongside oral corticosteroids (OCSs) in treating asthma exacerbations.Methods This retrospective cohort study included individuals from the Netherlands between 1994 and 2022 from the IADB.nl pharmacy dispensing database. Individuals had to be 16–45 years old, use inhaled asthma medication and have a first recorded prednisone/prednisolone (OCS) dispense of ≥30 mg/day for 3–14 days. Patients were compared regarding treatment failure (a new dispense of OCS or antibiotics, 15–30 days after initial dispense), based on whether or not they were dispensed antibiotics (AB) alongside their first recorded OCS dispense. Regression analyses with inverse probability of treatment weighting were used to adjust for various confounders.Results Of the 5401 individuals included, 38% received antibiotics alongside the first-recorded OCS dispense, with a decreasing trend from 47% in 2009 to 24% in 2020. The OR for treatment failure was 1.36 (95% CI 0.81 to 2.16) for AB+OCS versus OCS-only. The HR for a new exacerbation within 31–365 days of follow-up was 1.20 (95% CI 0.92 to 1.56) for AB+OCS versus OCS-only. The lack of beneficial effect of AB was consistent across subcohorts.Conclusions This study found no reduction in treatment failure, nor in risk of subsequent exacerbation, from adding AB to OCS for treating acute asthma exacerbations. We suggest that antibiotics should not be used in primary care settings to treat acute asthma exacerbation unless there are clear signs of bacterial infection.