Background: Amitriptyline has a lengthy track record of success in treating depression. It is used less frequently due to its extensive side-effects including anticholinergic side effects, oxidative stress and high toxicity in over dose. Ashwagandha is an essential ancient herb having anti-depressant, antioxidant properties. Aim of study: To evaluate the histological effects of Ashwagandha& Amitriptyline on the salivary glands in rats. Material and Methods: forty healthy albino rats that were 8-10 weeks old and weighed 200-250 g were apportioned into four groups randomly. Group I (Control) received distilled water for 30 days. Group II received amitriptyline (10mg/kg) orally. Group III was given ashwagandha root extract (200mg/kg) orally and Group IV was given a combination of amitriptyline (10mg/kg) orally and ashwagandha root extract (200mg/kg) orally for 30 days. Rats were euthanized at the end of 30 days. Submandibular glands were dissected, stained with hematoxylin & Eosin and examined histologically. Results: The Histological examination of the submandibular glands tissue showed that, group II exhibited eosinophilia, atrophy and necrosis of the cells and congested blood vessels. Group III exhibited a normal architectural picture. Group IV exhibited necrosis and degradation of epithelial cells lining granular convoluted tubules, atrophy in acini lobules and congestion of blood vessels. Conclusion: Amitriptyline induced degeneration of Submandibular glands in rats after 30 days of treatment. Ashwagandha alone has protective effects on salivary glands. But, Ashwagandha will interact with Amitriptyline causing further degeneration of Submandibular glands as a result of the Fenton reaction.