Simple SummaryRadiotherapy, commonly used to treat thoracic cancers, can induce adverse effects in the surrounding normal tissue, which become dose limiting factors and narrow the therapeutic window. Polyphenols, a type of natural plant compounds, have been proposed to radiosensitize the tumor and, at the same time, protect the normal tissue against radiotherapy-induced adverse effects. This review summarizes the current knowledge of the radioprotective effects of polyphenols, especially on normal thoracic tissues, and their underlying molecular mechanisms.AbstractRadiotherapy is one of the standard treatment approaches used against thoracic cancers, occasionally combined with chemotherapy, immunotherapy and molecular targeted therapy. However, these cancers are often not highly sensitive to standard of care treatments, making the use of high dose radiotherapy necessary, which is linked with high rates of radiation-induced adverse effects in healthy tissues of the thorax. These tissues remain therefore dose-limiting factors in radiation oncology despite recent technological advances in treatment planning and delivery of irradiation. Polyphenols are metabolites found in plants that have been suggested to improve the therapeutic window by sensitizing the tumor to radiotherapy, while simultaneously protecting normal cells from therapy-induced damage by preventing DNA damage, as well as having anti-oxidant, anti-inflammatory or immunomodulatory properties. This review focuses on the radioprotective effect of polyphenols and the molecular mechanisms underlying these effects in the normal tissue, especially in the lung, heart and esophagus.