Background: A blood transfusion is an emergency operation for very ill newborns. Nursing care is required for preparation before, during, and after the procedure in addition to ongoing medical competence for life-saving interventions. Clinical practice and classroom learning are connected through simulation-based education. It helps nurses become competent before dealing with newborns in a real-world setting, raising the standard of care and assuring the safety of the infants. This study aimed to determine the impact of simulation-based training on nurses' performance and satisfaction regarding blood transfusion at the neonatal intensive care unit. Method: A quasi-experimental research design was used to achieve the aim of the current study. Setting: The study was conducted in the Neonatal Intensive Care Unit affiliated at Sohag University Hospital. Subjects: Included all nurses (50) who are working in the neonatal intensive care unit. Tools for data collection: (1) Structured interview questionnaire sheet (2) observational checklist, and (3) Nurses' satisfaction scale was used to collect data. Results:  In terms of knowledge, practice, and satisfaction, there was a very statistically significant difference among the nurses. The study's findings showed that, before the implementation of the simulation-based training, more than two-thirds of the nurses were poorly informed about blood transfusions, and more than half of them had incompetent levels of practice in this area. Following the implementation of simulation-based training, the vast majority of the examined nurses had a good level of knowledge and the majority of them had a competent level of practice. When compared to pre-training, nurses' performance showed a very statistically significant difference and improvement. Conclusion: According to the findings of the current study, simulation-based training enhanced nurses' performance and satisfaction with blood transfusion. Recommendations: The study suggested that simulation-based training be used as an effective technique for teaching nurses about blood transfusion.