Introduction Inflammation of the oral mucosa is one of the conventional side effects of chemotherapy, affecting the patient's acceptance and treatment process. Hence, the knowledge regarding the complication and the methods to prevent them helps improve the course of treatment, prevent frequent hospitalizations, and survive these patients. The current study aims to implement the family-centered empowerment model based on mucositis management on the quality of life of children with cancer undergoing chemotherapy. Method A randomized study is presented in this paper that is conducted on 60 parents of children with cancer undergoing chemotherapy. These children were referred to Shahrekord Kashani Hospital in 2019–2020. The authors received informed consent from the parents who also participated in the tests. The parents were selected using the available sampling method and divided into two intervention and control groups through random allocation. In the intervention group, based on the empowerment model of the Al-Hani family, the intervention's content was consolidated in person and virtual space. Whereas in the control group, routine training was provided by nurses. To collect data from the demographic information questionnaire, the children's quality of life questionnaire was considered based on the parents' point of view. Ped QL Cancer Modules were used, which were electronically provided to the control and intervention groups in the three stages before, immediately after, and three months after the end of the intervention. Besides, who oral mucositis grading scale was employed for measuring mucositis. The collected data were analyzed using descriptive, analytical, and statistical tests (frequency and percentage, mean and standard deviation, and Fisher's exact test) and using SPSS23 software. Findings The obtained results revealed that the children's quality of life in the two groups immediately and three months after the intervention had a significant difference (p < 0.001). Accordingly, the quality of life of the children in the intervention group (35.12 ± 66.30) represented a significant rise (p < 0.001) compared to the control group (-4.6 ± 7.6). Conclusion The results indicated that the empowerment program could help parents discover the reality and increase awareness, ability, skill, and critical thinking. Therefore, the obtained results can prevent complicating the inflammation of the oral mucosa in children undergoing chemotherapy. Reducing hospitalization due to chemotherapy complications will improve children's quality of life.