Myocardial fibrosis represents a common pathological hallmark of various cardiovascular diseases progressing to heart failure, with the immunoinflammatory response playing a pivotal role in the pathogenesis of myocardial fibrosis. Accumulating evidence suggests that the immune microenvironment modulates myocardial fibrosis by regulating RNA epigenetic modifications, with 5-methylcytosine (m5C) methylation emerging as a key player in this process. This review systematically summarizes the characteristics of m5C methylation modification, the regulatory enzymes involved, and their biological functions in immunoinflammatory responses and myocardial fibrosis. Furthermore, this review examines the molecular mechanisms underlying m5C methylation-mediated regulation of myocardial fibrosis, encompassing the activation of immune cells, the transdifferentiation of cardiac fibroblasts, and the regulation of collagen metabolism. Moreover, the potential clinical implications of targeting m5C methylation for treating myocardial fibrosis are discussed, with an emphasis on future therapeutic prospects.