Background: Dry eye disease (DE) is an emergent global disease which was aggravated by working from home during the COVID-19. Alpha-Lipoic Acid (ALA) is a natural potent universal antioxidant. Aim: The current study was done to assess the effect of ALA on the cornea of an experimentally induced DE. Methods: Forty adult male albino rats were randomly divided into four main groups: group I (control), group II received 100 mg/kg ALA orally once daily for six weeks, group III(DE) received topical administration of 0.2% Benzalkonium chloride (BAC) solution twice daily for 14 days, group IV (DE-ALA) received BAC and ALA on 15^th day of experiment in the same dose and duration as group II and III respectively. Results: DE group showed break up of tear film, apoptotic corneal epithelium, and neovascularization in stroma. Ultrastructurally, corneal epithelial cells showed swollen mitochondria, dilated RER, and depleted surface microplicea as well as attenuated desmosomes in between them. A high significant increase was observed in the mean total corneal thickness, immunoreactivity of MMP-9 & VEGF as well as the number of Ki-67 positive cells. Also, a high significant decrease in the corneal epithelial thickness, mean area percentage of collagen fibers, and the mean goblet cells number in the conjunctiva were noticed. The ameliorative effect of ALA against the histopathological alterations induced by DE was corroborated by current histological, immunohistochemical, and ultrastructural results of DE-ALA group. Conclusion: Oral administration of ALA ameliorates the biochemical, and histopathological changes in the cornea of the induced DE model.