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Radiation-induced myocardial fibrosis (RIMF) is a potentially severe lethal clinical complication after chest radiotherapy (RT), which is the major common denominator of radiation-induced heart disease (RIHD). RIMF is characterized by decreased ventricular elasticity and distensibility, resulting in decreased ejection fraction and heart failure, and even sudden cardiac death, which impairs the long-term health of post-RT survivors and limits dose and intensity of RT required to effectively kill tumor cells. Although the exact mechanisms involving in RIMF are not clear, overwhelming evidence indicates that the occurrence of RIMF is related to various cells, regulatory molecules, and cytokines. And accurately diagnosing and identifying patients who may progress to RIMF is challenging. Despite the urgent need for an effective treatment, there is no medical therapy for RIMF approved for routine clinical application. In this review, we have focused on the underlying pathophysiology that is critically involved in the initiation and progression of RIMF and then outlined potential preventative and therapeutic strategies to counter this toxicity, providing a basis for therapeutic strategies of RIMF.