The present paper aims to analyze the resistance of Helicobacter pylori (H. pylori) infected by children in Shanghai from 2019 to 2020 to four commonly used antibacterial drugs. From January 2019 to October 2020, 1 605 children who came to Children’s Hospital of Fudan University in Shanghai and received gastroscopy and rapid urease test were selected. Gastric mucosal membrane samples were collected for H. pylori isolation, culture and identification. In vitro drug susceptibility test by E-test method was used to analyze H. pylori resistance in children in different age groups. The results showed that the overall positive rate of H. pylori of the enrolled children was 31.5% (506/1 605), and there was no difference in gender and age. The resistance rates of clinical H. pylori isolates to metronidazole, clarithromycin, levofloxacin, and amoxicillin were 42.3%, 25.1%, 8.1%, and 3.0%, respectively. Except that the resistance rate of H. pylori to clarithromycin in children aged 13-16 years (31.2%) was significantly higher than that of children aged 1-3 years (13.3%) (P＝0.040), there was no difference in age and gender. In addition, the double resistance rate of H. pylori to clarithromycin＋metronidazole was 18.0%, which was significantly higher than that to clarithromycin＋levofloxacin (5.1%), metronidazole＋levofloxacin (4.9%), metronidazole＋amoxicillin (1.4%) and amoxicillin＋levofloxacin (0.8%) (χ2＝172.706, P<0.01). Multi-drug resistance analysis showed that the resistance rate of H. pylori to levofloxacin＋clarithromycin＋metronidazole was 3.0%, which was significantly higher than that to levofloxacin＋amoxicillin＋clarithromycin (0.6%), amoxicillin＋metronidazole＋levofloxacin (0.6%) (χ2＝13.907, P＝0.01). It is suggested that H. pylori isolated from children in Shanghai from 2019 to 2020 has a higher resistance rate to metronidazole and clarithromycin, a lower resistance rate to amoxicillin and levofloxacin, and a higher dual resistance rate to metronidazole and clarithromycin.