Radiation-induced fibrosis (RIF) is a severe long-term complication of the normal tissue following radiotherapy. Its prototypical characteristic is the persistent activation of myofibroblasts, resulting in proportion disorder and hyperplasia remodeling of the extracellular matrix comprising collagen. The continuous progress of RIF may contribute to multiple clinical manifestations such as hollow organ stenosis, impaired gaseous diffusion, and loss of tissue compliance significantly affecting the overall quality of daily life in patients with irradiated cancer. Traditionally, the potential mechanism of myofibroblast activation and differentiation has not been elucidated, and the process has been considered as static and irreversible. Recent studies have shown that RIF is a dynamic, multi-step process mediated by many regulated chemokines and cytokines. The RIF process includes release of reactive oxygen species (ROS), microvascular injury, recruitment of inflammatory cells, and activation of myofibroblasts. Numerous signaling pathways are involved in the initiation and progression of RIF, of which SMAD-regulated CTGF expression mediated by TGF-β1 is referred as the main axis. Current management strategies applied in clinical practice for patients with RIF are only supportive treatments, such as anti-inflammatory therapy using steroids; however, the efficacies achieved by these interventions are limited and unsatisfactory. Therefore, this review explores advances in RIF pathogenesis and anti-fibrosis therapy. We hope to provide clinicians with improved awareness and enormous promise in the management of RIF.