Methotrexate (MTX), a chemotherapeutic drug, causes severe cytotoxic effects on lingual mucosa. Pomegranate peel extract (PPE) and pumpkin seed oil (PSO) are natural substances, that are used to decrease the toxic effect on tissues because of their anti-oxidant effects. Aim of the study: The current study was conducted to evaluate and compare between the preventive role of pomegranate peel extract and pumpkin seed oil against cytotoxicity induced by methotrexate on albino rats' lingual mucosa. Methodology: This investigation involved 32 adult male albino rats, which were evenly distributed into four groups, each containing eight rats: control, MTX, PPE+MTX, and PSO+MTX. Following a duration of 21 days, all the animals were humanely euthanized. Their tongues were then collected and subjected to staining with Hematoxylin & Eosin (H&E) and immunohistochemical analysis for PCNA. Results: MTX group revealed markedly atrophic degenerative changes in lingual papillae, lamina propria showed degeneration and dissociation of collagen fibers, inflammatory cell infiltrations and acinar and ductal degeneration compared to control group. However, PPE and PSO groups showed fewer damaging effects on tongue papillae comparing to MTX group only. PCNA was significantly increased in PPE and PSO groups compared to MTX group. Conclusions: Pomegranate peel extract showed obvious improvement against methotrexate degenerative effect than pumpkin seed oil which demonstrated poor improvement thus, PPE was outstanding anti-inflammatory and anti-oxidant than PSO