Abstract: Ionizing radiation impairs ovarian function by inducing DNA double-strand breaks, oxidative stress, and inflammatory cascades, leading to primordial follicle depletion and premature ovarian insufficiency (POI). Core mechanisms involve ATM/p53-mediated DNA damage response, granulosa cell apoptosis triggered by a sharp increase in reactive oxygen species/reactive nitrogen species (ROS/RNS), and Toll-like receptor (TLR)/NF-κB-driven chronic inflammation. Currently, only amifostine and palifermin are internationally approved radioprotective agents, yet they exhibit significant limitations including severe toxicity, narrow indications, and lack of conclusive evidence for ovarian protection. Investigational agents like the natural antioxidant melatonin require further clinical validation for ovarian radioprotection. Emerging strategies, such as TLR5 agonists, mitochondrial-targeted agents, and targeted drug delivery systems, provide novel directions for mitigating radiation-induced ovarian injury. This review synthesizes key pathways of radiation-induced ovarian damage, explores cutting-edge mechanisms, and highlights promising novel radioprotective agents. The proposed synergistic “epigenetic regulation + immunomodulation” strategy embodies a paradigm shift from passive mitigation to active precision protection against ovarian radiation damage.