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Radiotherapy is essential in cancer treatment, using ionizing radiation to generate free radicals in the irradiated tissue or to directly damage DNA. Despite comprehensive safety measures, healthy tissue is also irradiated, causing side effects like oral mucositis and dermatitis. Antioxidants, which are known for scavenging free radicals, may reduce these adverse effects, but their impact on radiotherapy efficacy remains unclear. The aim of this systematic review was to evaluate the influence of antioxidant supplementation on radiation-induced side effects, tumor outcome and quality of life. In April 2024, a systematic research was conducted searching five databases (Medline, CINAHL, EMBASE, Cochrane CENTRAL, PsycINFO) to find studies looking at the effect of antioxidant supplementation during radiotherapy on radiation-induced side effects and parameters of tumor outcome or survival. Antioxidants can mitigate radiation-induced side effects, with vitamins C and E showing positive effects on oral mucositis, xerostomia and cardiac function. Curcumin and EGCG improved symptoms such as mucositis, dermatitis and esophagitis, while glutathione-enhanced treatment compliance but did not provide significant protection against side effects. However, multiple studies indicate that the concurrent use of antioxidants during cancer treatment may impair tumor control, increase recurrence rates and reduce survival outcomes. Antioxidants may reduce radiation-induced side effects but could compromise treatment efficacy. Due to inconsistent evidence and potential risks, clinical recommendations are premature. Further high-quality research is needed.