Background: The application of the comfort theories model as a comprehensive element of nursing intervention plays a significant role in the improvement of children’s experiences during their hospitalization for SCD crises. Aim and Design: The true experimental design approach was used to investigate the efficiency of comfort theory in improving the comfort level model for children with SCD crises. Sample and setting: A convenience sample was taken from a group of pediatric with sickle cell disease crises, were admitted in pediatric inpatient department of Benha University Hospital and Specialized Children Hospital, Benha city, Egypt. Data collection tool: Data collection was undertaken in a number of ways, including a demographic information form, patient Comfort Behaviors Checklist, Comfort Daisies Scale, and General Comfort Questionnaire, both pre- and post-theory intervention, based on the nursing process. Results: When compared to a control group, significant differences were observed in children with SCD crises post-comfort theory application. There was also a positive correlation between the children’s state of comfort and post-comfort theory intervention. An association was also noted between children in secondary education 2 and at a higher economic level in comfort state at second observation, which was deemed to be the best comfort achievement. Conclusion and recommendations: based on the results of this study imply that the comfort theory-based care model plays an effective role in the improvement of comfort levels for children with sickle cell crises who are hospitalized. It is therefore recommended that nurses must consider a pediatric comfort needs from a physical, psychological, spiritual, cultural-social and environmental point of view, prior to carrying out any nursing procedure, and apply the comfort care theory model to alleviate the patient’s discomfort.