ABSTRACT: Objective: To evaluate the effect of melatonin as a protective treatment for the tongue in irradiated rats. Materials and Methods: Male Sprague Dawley rats were subjected to a single session of 50 Gy radiation and treated with melatonin 30 minutes before and after the radiotherapy session. A clinical evaluation was carried out a week and a half, third- and sixth-week post-treatment; finally, a tongue biopsy was taken for a histopathological study in the third and sixth weeks after radiation. Results: Clinical evaluation shows a clear trend, that preventive administration of melatonin could facilitate the recovery of mucosal tissue after radiation. Additionally, cellular infiltrate was 40% fewer in the melatonin-treated group compared to the control, as well as the number of the congested vessel were fewer. Conclusion: These findings showed for the first time the preventive role of melatonin in the tongue mucosa reducing the changes associated with mucositis, inflammatory infiltrate, and congestive blood vessels.