Due to the adverse effects of their disease, patients with thalassemia major face many problems such as a lack of proper growth, enlarged spleen and liver, bone disorders, especially the bones of the head and face. As a result of the long treatment process of this disease, other aspects of their life are also affected. The physical and mental problems in this population of patients will lead to frustration and lower social performance and quality of life. The present study aimed to explore the effect of an educational intervention based on the PRECEDE model on quality of life of adults with thalassemia major in Hormozgan province. The present quasi-experimental study was conducted on 234 adults with major thalassemia who visited the thalassemia medical centers in Hormozgan province in 2022. The participants were selected through a simple randomization from two cities of Hormozgan province (Bandar Abbas as the intervention group and Minab as the control). Each group had an equal number of participants (n = 117). The data were collected using a demographic information questionnaire, a researcher-made questionnaire based on the model constructs and the SF-12 quality of life questionnaire. The instruments were once administered before the intervention and once again 4 months after the intervention. The educational intervention included 3 sessions a week, each 60 min in length, shared in WhatsApp and Telegram. The data were analyzed in statistical package for the social sciences version 24 using Mann-Whitney U-test, chi-square test, Wilcoxon's test, and analysis of covariance. The results showed that after the educational intervention, the mean scores of knowledge, attitude, self-efficacy, enabling afctors, reinforcing factors and the mean score of overall quality of life increased significantly in the intervention group compared to the control (p < 0.05). The covariance analysis showed when the effect of the pretest score is removed, the mean scores of the model constructs and the quality of life are significantly different in the two groups. Educational interventions based on the PRECEDE model can help identify factors affecting the quality of life on many aspects in patients with thalassemia major. Thus, these interventions help improve patients' quality of life. The present findings can guide health policy makers and experts use modern educational interventions to develop the educational content to promote a healthy lifestyle and self-management in certain diseases such as thalassemia major.