Abstract Background: Adolescents with thalassemia major face many challenges in adjusting to their illness. Self-efficacy is a highly valuable modifiable construct for adolescents' adjustment. Coping with thalassemia major is best when they demonstrate high self-efficacy. This study aimed to assess the effect of an educational program on self-efficacy of adolescents with thalassemia major. A quasi-experimental research design was used to perform this study. A convenience sampling of (80) adolescents with thalassemia major attending the Thalassemia Center at Assiut University Children Hospital was selected. Data were collected using two tools; Tools (1):- A structured Questionnaire Interview Sheet, Tool (2):- The Self-Efficacy Scale. Results revealed that most (82.5%) of the adolescents in the study group had moderate self-efficacy after implementing the educational program to only 27.5 % in the control group. The study results reported a highly statistically significant difference between the studied adolescents' knowledge level and their self-efficacy level (p= 0.00). Conclusion: The present study highlighted the effectiveness of the educational program on enhancing self-efficacy of adolescents with thalassemia major. So, the study recommended that the health education programs must be held frequently for adolescents with thalassemia major to increase their knowledge about the disease and how to cope with it.