Orientation program promote the knowledge and skill level of new graduated nurses in providing patient care. Therefore organizations need to support effective orientation programs that are structured to prepare and facilitate the transition of a new graduated nurse to competency to improve patient safety. Aim: To investigate effect of orientation program about patient safety on new graduated nurses ́ knowledge and skills at Main Mansoura University Hospital. Design: A quasi-experimental research design was utilized. Setting: All in patient departments at Main Mansoura University Hospital participated in the study. Subject: The study was include all new graduated nurses (n=80) who are available during the time of data collection at Main Mansoura university hospital. Tools: (I) Orientation Program Knowledge test. (II) Patient safety skills checklist. Results: During various stages of the training program, there were statistically significant differences in the levels of knowledge of newly graduated nurses regarding patient safety. Additionally, during various stages of the training program, all patient safety skills among newly graduated nurses were statistically significant. Additionally, there was no statistically significant relationship between newly graduated nurses' patient safety knowledge and abilities at various program levels. Conclusion: The post and follow-up new graduated nurses' patient safety knowledge and skills have improved after program implementation. Recommendations: Developing patient safety training programs and continuous updating of new nurses' knowledge and skills.