Bacterial resistance to antibiotics is a global concern. The objective is to present trends in resistance rates to third-generation cephalosporins (3GC) and fluoroquinolones (FQ) in urinary isolates of Escherichia coli reported by private clinical laboratories participating in the Primo national surveillance program between 2015 and 2019. A decrease in resistance to 3GCs was observed between 2015 and 2018 (4.2% vs. 3.2%), followed by an increase in 2019 (3.4%). The percentage of extended-spectrum beta-lactamase (ESBL)-producing strains followed the same trend (3.7% in 2015, 2.8% in 2018, and 3.0% in 2019). The percentage of fluoroquinolone (FQ) resistance also decreased between 2015 and 2018 (12.5% vs. 11.0%) and increased in 2019 (11.4%). Over the period, a decrease in the percentages of ESBL-producing and fluoroquinolone-resistant E. coli was observed in the Auvergne-Rhône-Alpes, Brittany, Centre-Val de Loire, Grand-Est, Normandy, Nouvelle-Aquitaine, and Pays de la Loire regions. In Île-de-France, a non-significant increase in the percentage of ESBL-producing E. coli was observed between 2016 and 2019, while resistance to FQs decreased between 2017 and 2019. In the Provence-Alpes-Côte d'Azur and Occitanie regions, resistance to C3G and FQ increased between 2017 and 2019. The trend in resistance to C3G and FQ is encouraging, and the data generated by the Primo surveillance program can guide the actions of future Regional Centers for Antibiotic Therapy (CRAtb).