Background: 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. The use of simulation for teaching the knowledge, skills, and behaviors necessary for effective neonatal resuscitation has seen widespread growth and adoption across pediatric institutions. This study aimed to determine the effect of simulation-based resuscitation education on nurses' performance and self-efficacy regarding neonatal resuscitation. Method: A quasi-experimental research design (pre and post-test one group) was used. Setting: The study was conducted in the Neonatal Intensive Care Unit affiliated to South Valley University Hospital. Subjects: Included a convenient sample of all nurses (50) working in the neonatal intensive care unit. Tools for data collection: Tool (I): Nurses' personal data assessment sheet, Tool (II): Neonatal resuscitation nursing knowledge, Tool (III): Standardized Checklist for Neonatal Resuscitation adopted from (American Heart Association, 2015), and Tool (IV): Self-efficacy assessment was used to collect data. Results:  There was a highly statistically significant difference between the studied nurses' knowledge, practice, and self-efficacy.    The study results revealed that more than three-quarters of studied nurses had an unsatisfactory level of knowledge, and more than half had an incompetent level of practice regarding neonatal resuscitation pre-to-simulation-based resuscitation education implementation. The vast majority of the studied nurses had a satisfactory level of knowledge and most of them had a competent level of practice post simulation-based resuscitation education implementation. There was a highly statistically significant difference and improvement in nurses' performance after simulation-based resuscitation education than pre-education. Also, the study revealed a marked increase in nurses' total self-efficacy post-implementation compared to the pretest with statistically significant differences. Conclusion: The present study concluded that simulation-based resuscitation education had a significant effect on improving nurses' performance and self-efficacy regarding neonatal resuscitation. Recommendations: The study recommended that simulation-based education for nurses who are in close contact with neonates once with reevaluation and feedback after each update is very important as an effective method in nurses' training regarding neonatal resuscitation.