Background: Oral mucositis (OM) is a common debilitating side effect induced by methotrexate (MTX). Quercetin (QRC) is a natural flavonoid with anti-inflammatory and antioxidant properties. Formulating QRC in nanoemulsion (QRC-NE) may enhance its biological effects and therapeutic potential. Aim: This study evaluated the histopathological and immunohistochemical effects of QRC-NE on MTX-induced lingual mucositis in albino rats. Material and Methods: Fifty animals were randomly divided into five groups: Negative control (healthy), MTX-treated (a single i.p. 20 mg/kg on day 11), QRC-treated (50 mg/kg orally, 16 days), QRC+MTX and QRC-NE+MTX (QRC 50 mg/kg and QRC-NE 12.5 mg/kg, respectively, orally as a prophylactic to OM, 16 days + MTX a single i.p. 20 mg/kg on day 11). Rats were euthanized on day 17. The anterior two-thirds of tongue specimens were processed for histological assessment by H&E and Masson Trichrome staining, and Caspase-3 IHC expression. Data were analyzed using the one-way ANOVA and Bonferroni post-hoc tests. Results: MTX group revealed marked histological destruction in the lingual mucosa with reduced collagen density and strong caspase-3 expression compared to the negative control (p≤0.05). QRC-NE treatment showed significantly preserved mucosal architecture, increased 
collagen density, and exhibited mild caspase-3 expression compared to MTX (p≤0.05). Conclusions: QRC-NE has a modulatory effect on MTX-induced lingual mucositis, suggesting a potential role for nano-based QRC administration in alleviating oral mucosal injury.