Introduction: Thalassemia major is one of the most common genetic diseases in humans that causes many problems for the patient, family, and health system. This study aimed to determine the impact of an empowerment program on the knowledge and performance of the family of children with thalassemia major referring to the Special Patients Center of Birjand in 2016. Methods: This quasi-experimental study (pretest-posttest design with a control group) incorporated 60 eligible mothers of children with thalassemia major referring to Birjand Special Patients Center in 2016. The mothers were selected via convenience sampling method and were randomly assigned to experimental (n = 30) and control (n = 30) groups. The experimental group went through an intervention that was developed based on the steps of the empowerment model. The sessions ranged between 3 and 5 sessions, depending on the participant, and were presented as a group discussion, along with pamphlets and slides about the disease. Mothers in the control group did not receive any intervention. Researcher-made knowledge and performance questionnaires were used to collect data, which were completed by mothers of both groups before and after the intervention. Data were analyzed in SPSS-22 statistical software, using Chi-square, Fisher’, s exact test, independent t-test, paired t-test, Mann-Whitney, and Wilcoxon tests. The level of significance was set at p ≤, 0. 05. Results: The results showed that in the experimental group, the post-intervention mean score of total knowledge and overall performance were significantly increased compared to baseline (p <0. 05). On the contrary, in the control group, the mean score of total knowledge and overall performance was not significantly different from baseline (p> 0. 05). The mean score changes in total knowledge overall performance in mothers of the experimental group were significantly higher than those of the control (p <0. 01). Conclusions: Based on the results, the implementation of the empowerment model is one of the most important approaches to increase the knowledge and performance of mothers of children with thalassemia major and leads to better and more efficient care and overall improvement in the lives of these patients.