© 2022, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.Radiotherapy can be employed as a therapeutic modality alone in the early stages of cancer and is used together with other treatments such as surgery and chemotherapy in more advanced stages. However, exposure to ionizing radiation in association with radiotherapy affects several organs in the head and neck and can give rise to early and late side effects. Exposure to ionizing radiation used in radiotherapy is known to cause cell damage by leading to oxygen stress through the production of free oxygen radicals (such as superoxide radicals, hydroxyl radical, hydrogen peroxide, and singlet oxygen), depending on the total radiation dosage, the fractionation rate, radiosensitivity, and linear energy transfer. The purpose of the present study was to determine the potential protective role of a powerful and highly selective α2-adrenoreceptor agonist with a broad pharmacological spectrum against salivary gland damage induced by ionizing radiation exposure. Forty Sprague–Dawley rats were divided into five groups—control, ionizing radiation, ionizing radiation + dexmedetomidine (100 µg/kg), ionizing radiation + dexmedetomidine (200 µg/kg), and ionizing radiation + amifostine (200 mg/kg). Following exposure to ionizing radiation, we observed necrosis, fibrosis, and vascular congestions in parotid gland epithelial cells. We also observed increases in malondialdehyde (MDA) and cleaved Caspase-3 levels and a decrease in glutathione (GSH). In groups receiving dexmedetomidine, we observed necrotic epithelial cells, fibrosis and vascular congestion in parotid gland tissue, a decrease in MDA levels, and an increase in GSH. Dexmedetomidine may be a promising antioxidant agent for the prevention of oxidative damage following radiation exposure.