It is crucial to understand the trends in paediatric antibiotic prescribing and serious and nonserious infections to improve antibiotic prescribing practices for children in ambulatory care. Assessing trends in paediatric antibiotic prescribing and infection incidence in general practice from 2002 to 2022. In this retrospective cohort study using INTEGO network data from 162 507 patients in Flanders (Belgium), we calculated antibiotic prescribing rates and proportions alongside incidence rates of serious and nonserious infections, stratified by age (0-1, 2-6, 7-12 years) and municipality. We performed autoregressive moving average time-series analyses and seasonality analyses. From 2002 to 2022, antibiotic prescribing rate decreased significantly: 584/1000 person-years (PY) (95% CI 571-597) to 484/1000PY (95% CI 478-491); so did antibiotic overall prescribing proportion: 46.3% (95% CI 45.1-47.6) to 23.3% (95% CI 22.9-23.7) (59.3% amoxicillin and 17.8% broad spectrum). Prescribing proportions dropped significantly for nonserious (45.6% to 20.9%) and increased for serious infections (64.1% to 69.8%). Proportions significantly dropped for acute suppurative otitis media (74.7% to 64.1%), upper respiratory tract infections (44.9% to 16.6%), bronchitis/bronchiolitis (73.6% to 44.1%) and acute tonsillopharyngitis (59.5% to 21.7%), while significantly increasing for pneumonia (65.2% to 80.2%). Nonserious and serious infection incidence rates increased from 785/1000PY and 34.2/1000PY to 1223/1000PY and 64.1/1000PY, respectively. Blood and CRP testing proportions increased significantly. Antibiotic prescribing in general practice for children declined from 2002 to 2022. Further targeted antibiotic stewardship initiatives are needed to reduce the use of broad-spectrum antibiotics and antibiotic prescribing for conditions such as otitis media and bronchitis/bronchiolitis.