Background: Peripherally inserted central catheter is an essential device used frequently in neonatal intensive care units for critically ill neonates who need continuous monitoring and resuscitation treatments. Simulation-based education serves as a link between classroom learning and clinical practice. It aids nursing competency before working with neonates in a real-life environment, hence improving the quality of care and ensuring neonates' safety. This study aimed to: evaluate the effect of simulation-based education on nurses' performance and satisfaction regarding peripherally inserted central catheters in the Neonatal Intensive Care Unit. Subject and Method: Design: A quasi-experimental research design was used. Setting: The study was conducted in the Neonatal Intensive Care Unit affiliated to Sohag University Hospital. Subjects: all nurses (50) who are working in the neonatal intensive care unit. Tools for data collection: (1) peripherally inserted central catheter questionnaire sheet, (2) observational checklist, and (3) nurses' satisfaction scale was used to collect data. Results: There was a highly statistically significant difference between the studied nurses' knowledge, practice, and satisfaction. The study result revealed that more than two-thirds of studied nurses had a poor level of knowledge, and more than half of them had an unsatisfactory level of practice about peripherally inserted central catheters before implementation of the simulation-based education. The vast majority of the studied nurses had a good level of knowledge and most of them had a satisfactory level of practice after implementing simulation-based education. There was a highly statistically significant difference and improvement in nurses' performance after simulation-based education than pre-education. Conclusion: The present study concluded that simulation-based education had a positive effect on improving nurses' performance and satisfaction regarding peripherally inserted central catheters. Recommendations: The study recommended that simulation-based education should be integrated as an effective method in nurses' training about peripherally inserted central catheters.