Background: The most prevalent inherited genetic illness in children is sickle cell disease (SCD). As they deal with the difficulty of recurrent painful exacerbations or crises, which can be life-threatening, children and adolescents with sickle cell disease may be at risk for psychological distress, including depression and low self-efficacy (Benton, Boyd, Ifeagwu, Feldtmose, and Smith-Whitley, 2011). Objective: is to evaluate the effect of instructional based nursing intervention program on self-efficacy, depression and quality of life in children with sickle cell disease. Method: The research design was a quasi-experimental (pretest as well as posttest) one. Setting: The investigation was carried out at the Minia University Hospital for Obstetrics and Pediatrics  in pediatric hematology clinic. Sample: A purposive sample composed of 80 children with SCD from (10:18 years). Tools: fourth tools were utilized to collect data including, personal and clinical data sheet, Sickle cell disease self-efficacy (SCSES), Depression Self-Rating Scale for Children (DSRS-C), and World Health Organization Quality of Life-Brief (WHOQOL-BREF). Results: this study showed that there was positive improvement of children's level of self-efficacy and decreased depressive symptoms in post-test after 3months.also, children's knowledge and quality of life were enhanced in post/test after 3months with statistical significant difference between pre as well as post/test after 3months. Conclusion: The present study demonstrated that, instructional intervention program was effective in enhancing children self-efficacy which consequently decreasing depressive symptoms as well as  better quality of life also the higher knowledge level. Recommendations: developing a continuous instructional program for interacting children's with sickle cell anemia in better self-management behaviors.