COVID-19 restrictions have resulted in major changes in healthcare, including the prescribing of antibiotics. We aimed to monitor antibiotic prescribing trends during the COVID-19 pandemic in Dutch general practice, both during daytime and out-of-hours (OOH). Routine care data were used from 379 daytime general practices (DGP) and 28 OOH-services over the period 2019–2021. Per week, we analyzed prescription rates per 100,000 inhabitants, overall, for respiratory and urinary tract infections (RTIs and UTIs) specifically and within age categories. We assessed changes in antibiotic prescribing during different phases of the pandemic using interrupted time series analyses. Both at DGPs and OOH-services significantly fewer antibiotics were prescribed during the COVID-19 pandemic after government measures became effective. Furthermore, the number of contacts decreased in both settings. When restrictions were revoked in 2021 prescription rates increased both at DGP and OOH-services, returning to pre-pandemic levels at OOH-services, but not in DGP. Changes in antibiotic prescribing rates were prominent for RTIs and among children up to 11 years old, but not for UTIs. To conclude, while antibiotic prescribing decreased during the first year of the COVID-19 pandemic both in daytime and out-of-hours, the pandemic does not seem to have a lasting effect on antibiotic prescribing.