Background: The survival rate of neonatal giant omphaloceles has improved over the past 10 years, but the mortality rate remains at approximately 50% with traditional treatment. Delivery room surgery refers to a surgical procedure that is performed in the operating room to correct the structural defects of a newborn immediately after birth. Objectives: This study aimed to investigate the application of delivery room surgery for giant omphaloceles in East China. Methods: Neonates meeting the inclusion criteria of having omphalocele defects larger than 5 cm or of having most of the liver protruding into the sac were enrolled in this retrospective study. Data were evaluated specifically to determine the role of delivery room surgery in reducing the mortality of newborns with giant omphaloceles (GOs) and to identify factors that could optimize the conditions for traditional operations. A total of 52 newborns with GOs from two tertiary centres of paediatric surgery were identified. The patients were divided into two groups, the delivery room surgery group (group D) and the traditional operation group (group T), based on the perinatal management and time of surgery. Results: There was a significantly higher survival rate in the group D (77.8%) than in the group T (50%). The duration of ventilator use was 8.87 ± 10.12 days in the group D and 9.31 ± 7.75 days in the group T. The time of starting enteral nutrition was 12.88 ± 4.19 days in the group D and 16.75 ± 8.59 days in the group T. Newborns in the group T took more time to reach full enteral feeding. However, we did not find a significant difference in a comparison of the hospitalization time between the two groups (25.1 ± 18.1 days in the group D and 22.4 ± 11.1 days in the group T). Conclusions: The strategy of delivery room surgery appears to improve the survival of newborns with GOs and reduce family burden. A further reduction in mortality rates will depend on promoting the application of the delivery room surgical procedure.