Radiation-induced chronic wounds remain a major clinical challenge owing to persistent non-healing and progressive tissue degeneration. Rather than simply representing delayed wound repair, they arise from a self-perpetuating pathological cascade involving DNA damage, oxidative stress, chronic inflammation, microvascular dysfunction, cellular senescence, stem cell impairment, and fibrosis. Current clinical management remains largely supportive and symptomatic, with limited efficacy and no standardized therapeutic regimens targeting the core pathological mechanisms. Emerging strategies—antioxidant, antifibrotic, senolytic, stem cell/exosome-based, and functional biomaterial approaches—show promise. This review critically summarizes recent advances in pathogenic mechanisms and mechanism-based therapeutic strategies, highlighting current translational challenges and future directions for microenvironment-oriented regenerative therapies.