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Osteoarthritis (OA), the most common degenerative joint disease, is associated with severe functional limitation and impairment of quality of life. Numerous reports have documented the clinical efficacy of low-dose radiotherapy (LD-RT) in the management of various inflammatory disorders, including OA. In this paper, we assessed the clinical literature involving the use of LD-RT in the treatment of OA, its dose-response features, possible underlying mechanistic features, and optimal therapeutic dose range. We carried out a systematic review based on the guidelines of the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statements and evaluated articles meeting the inclusion criteria for this review. A total of 361 articles were identified from databases, such as Scopus, PubMed, Embase, and Science Direct out of which 224 articles were duplicates and were discarded. Of the remaining 137 articles, 74 articles were un-related, 27 articles were review articles, eight were conference abstracts, three were letters, two were editorials, two were notes, and one was a book chapter. Finally, 20 articles met all the inclusion criteria and were included in this systematic review. Several single-arm retrospective/prospective studies showed advantages for LD-RT in the management of OA in terms of pain relief, improvement of mobility and function, and showed minimal side effects. Mechanistic considerations involve positive subcellular effects mediated by the activation of a nuclear factor erythroid 2-related transcription factor (Nrf2) mediated antioxidant response. Further research on both the short- and long-term effects of LD-RT on OA and other inflammatory disorders is recommended. [ABSTRACT FROM AUTHOR]