Background: Family-centered empowerment model (FCEM) greatly values the motivational, psychological, and functional roles of children and their family members in health promotion. Its main goal is to strengthen the family system to promote children and family health. Aim: To investigate the effect of FCEM on knowledge and stress level among mothers of children with glucose-6-phosphate dehydrogenase enzyme deficiency(G6PD). Study design: A quasi-experimental design was performed. Setting: The study was conducted in hematology outpatient clinic at Mansoura University Children's Hospital. Subjects: a purposive sample composed of 60 mothers and their children who are suffering from G6PD deficiency. Tools: Two tools were used for data collection: Glucose-6-Phosphate Dehydrogenase Enzyme Deficiency Knowledge Questionnaire and Arabic version of Perceived Stress Scale. Results: There were an improvement in the mean score of mothers' total knowledge with statistically significant difference (P<0.001) in the post intervention phase compared to pre intervention phase. Mean score of mothers' stress level was 26.90 ± 6.26 pre the FCEM implementation and decrease to17.36 ± 2.73 post FCEM with a statistically significant difference. Conclusion: Applying FCEM on mothers of children with G6PD deficiency leading to improvement of their knowledge regarding G6PD and reduce their level of stress Recommendations: researchers recommended implementing FCEM for all mothers and their children with chronic diseases as a strategy for education and management.