Radiation-induced heart toxicity is one of the serious side effects after  a radiation disaster or radiotherapy for patients with chest cancers, leading to a reduction in the quality of life of the patients. Evidence has shown that infiltration of inflammatory cells plays a key role in the development of functional damages to the heart via chronic up-regulation of some pro-fibrotic and pro-inflammatory cytokines. These changes are associated with continuous free radical production and increased stiffness of heart muscle. IL-4 and IL-13 are two important pro-fibrotic cytokines which contribute to the side effects of exposure to ionizing radiation. Recent studies have proposed that IL-4 through upregulation of DUOX2, and IL-13 via stimulation of DUOX1 gene expression, are involved in the development of late effects of radiation. In the present study, we aimed to detect changes in the expression of these pathways following irradiation of rat’s heart. Furthermore, we evaluated the possible protective effect of metformin on the development of these abnormal changes. 20 male rats were divided into 4 groups (control, radiation, metformin-treated, metformin + radiation). These rats were irradiated with 15 Gy ⁶⁰Co gamma rays and sacrificed after 10 weeks for evaluation of the changes in the expression of IL4R1, IL-13R2a, DUOX1, and DUOX2. In addition, the levels of IL-4 and IL-13 cytokines, as well as infiltration of macrophages and lymphocytes were detected. Results showed an upregulation of both DUOX1 and DUOX2 pathways in the presence of metformin, while the level of IL-13 did not show any significant change. This was associated with infiltration of macrophages and lymphocytes. Also, treatment with metformin could significantly attenuate the accumulation of inflammatory cells, and upregulate these pathways. Therefore, suppression of dual oxidase genes by metformin may be a contributory factor to its protective effect.