Background: Blood transfusion is the direct administration of whole blood and/ or blood components Additionally, blood transfusions can pose a serious risk to life if safety precautions are ignored. Nurses play a dynamic role in the administration of blood transfusions, with correct and safe usage of blood and its components the probability of incidence of blood transfusion risks will be reduced to a minimum rate. This study aimed to evaluate the effectiveness of simulation-based training on nurses' performance, self-confidence, and satisfaction regarding blood transfusion. Research design: A quasi-experimental design (one group pre/ post-test design) was used. Setting: The study was carried out in the hematology unit, at Mansoura University Hospital.  Subjects:  All fifty available nurses who provide patients with direct clinical care in the previously selected settings have agreed to take part in the study. Three Tools were used for data collection: Tool I: A Structured Interviewing Questionnaire: Included nurses' socio-demographic characteristics and knowledge about blood transfusion that consisted of five parts: Part 1. Nursing activities before initiation of blood transfusion, Part 2. Nursing activities for initiation of blood transfusion, Part 3. Nursing activities during and after blood transfusion, Part 4. Adverse reactions of blood transfusion, and Part 5. Nursing management for blood transfusion adverse reactions, Tool II: Blood transfusion Observational Checklist and Tool III: Satisfaction and self-confidence in learning scale Results: There was a highly statistically significant difference between the studied nurses' knowledge, practice, self-confidence, and satisfaction.    The study result revealed that three-fifths of studied nurses had a poor level of knowledge, and more than half of them had an unsatisfactory level of practice about blood transfusion before the implementation of the simulation-based training. 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 training. There was a highly statistically significant difference and improvement in nurses' performance after simulation-based training than pre-training. Conclusion: The present study concluded that simulation-based training had a positive effect on improving nurses' performance, self-confidence, and satisfaction regarding blood transfusion. Recommendations: The study recommended that simulation-based training should be integrated as an effective method in nurses' education about blood transfusion.