Abstract Background Antibiotic resistance is mainly driven by (incorrect) use of antibiotics. Most antibiotics are prescribed in family medicine. Therefore, regularly monitoring of antibiotic prescriptions and evaluation of their (non-) prudent use in primary care is warranted. Objectives The aim of this study was to determine time trends in antibiotic prescriptions by Dutch family physicians (FPs) and to identify determinants of nonprudent antibiotic prescriptions by Dutch FPs. Methods Retrospective study among 27 Dutch general practices from the Research Network Family Medicine Maastricht, from 2015 to 2019. Results In total 801,767 patient years were analysed. Antibiotic prescriptions mainly increased in patients aged 65+ while prescriptions mainly decreased in patients below 65 years. Nonprudent antibiotic prescriptions decreased from 2015 to 2019 with the highest percentage of decline found in skin infections (66.9% [2015] to 53.9% [2019]). Overall, higher likelihood of nonprudent antibiotic prescriptions was found among men (odds ratio [OR] 4.11, 95% confidence interval [CI]: 3.91–4.33), patients aged 80+ (OR 1.44, 95% CI: 1.03–2.01; reference category ≤17 years), patients with comedication (OR 1.24, 95% CI: 1.17–1.31), and patients in urban general practices (OR 1.47, 95% CI: 1.38–1.56). Conclusions Antibiotic prescriptions increased over time in the elderly aged categories. Although an overall decrease in nonprudent antibiotic prescriptions was established from 2015 to 2019, percentages of nonprudent prescriptions remained high for skin infections and respiratory tract infections. Additionally, men, elderly aged patients (80+), patients with comedication and patients in urban general practices were more likely to receive nonprudent antibiotic prescriptions. Our results will help FPs to prioritize optimalization of antibiotic prescriptions in family medicine.