Oxidative stress is known to have a detrimental effect on wound healing following oral mucosal injuries. Exogenous antioxidant administration to restore redox balance has been proposed as a therapeutic approach to support wound healing after oral surgery. In our study, we evaluated the relative effectiveness of melatonin and alpha-lipoic acid in palatal wound healing, as well as the potential synergistic effect of their combined treatment. A full-thickness wound model was created on the palatal mucosa of 64 Wistar rats with a 5-mm punch biopsy. Experimental groups were intraperitoneally administered 60 mg/kg/day alpha-lipoic acid, 30 mg/kg/day melatonin, or their combination. The rats were sacrificed 5 and 10 days later to evaluate the wound healing, and palatal tissue samples were evaluated macroscopically, histologically, and immunohistochemically. On day 10, all experimental groups exhibited a significant reduction in wound surface area compared with the control group, with the combined group showing the greatest reduction. There was no significant difference between groups in granulation tissue amount and leukocyte density in hematoxylin-eosin-stained samples. Masson trichrome staining showed that collagen production was significantly higher in the combined group on day 10. Vascular endothelial growth factor (VEGF) immunoreactivity in wound edges was found to be increased in the combined group, being significant on day 5. Filaggrin expression was significantly higher on both days in the wound beds of all treatment groups, with the combined group exerting the highest increase. Our study shows that combined treatment of melatonin and alpha-lipoic acid may improve palatal wound healing process.