Background: Wilson's disease, which most frequently affects children or young adults and has a significant impact on children's quality of life, is the most frequent cause of improper excretion of copper from the body. The aim of the study was to evaluate the effect of comprehensive health promotion intervention on the quality of life among children with Wilson's disease. Methods: A quasi-experimental design was used. Setting: The research was carried out at the outpatient clinic of pediatrics at the National Liver Institute at Shebin Elkoom city. Sample: A purposive sample of 44 children with Wilson's disease was selected from the previously mentioned setting. Tools: three instruments were used for data Collection: a structured interview questionnaire, Precede- proceed model questionnaire, and the Pediatric Quality of Life Inventory (PedsQL) 4.0 Generic Core Scale. Results: the mean scores of all quality of life aspects (physical, emotional, social, and school functioning) of studied children had improved on the post and follow-up tests than on the pretest. As well, children with Wilson's disease who received comprehensive health promotion intervention based on the PRECEDE-PROCEED model had stronger predisposing factors, reinforcing and enabling factors on post and follow-up tests than on pretest. Conclusion: Comprehensive health promotion intervention was successful in improving the quality of life among children with Wilson's disease. Recommendation: This study recommended the integration of a model-based comprehensive health promotion intervention program, PRECEDE-PROCEED, into the outpatient clinic of pediatrics for children with WD and their families.