INTRODUCTION: About 80% of patients receiving chemotherapeutics suffer from side effects related to the gastrointestinal tract. Irinotecan (CPT-11) is a chemotherapeutic agent usually used in treating solid tumors. Quercetin (QRT), a bioflavonoid, is an antioxidant and scavenger reactive oxygen species scavenger. OBJECTIVE: The current study explored the possible protective effects of QRT against mucosal tongue injury caused by CPT-11. METHODS: The study included four equal groups: group 1/control, group 2/QRT, group 3/CPT-11, and group 4/CPT-11 + QRT. RESULTS: CPT-11-induced tongue injury in the form of non-healed ulcers, absent lingual papillae, mononuclear cells infiltration, marked deposition of collagen fibers, and overexpression of CD86 and tumor necrosis factor- α (TNF-α). The increased malondialdehyde levels, decreased superoxide dismutase and total antioxidant capacity revealed that there was an oxidative stress. Also, there was a decreased countenance of Ki-67 and Bcl-2 and an increased countenance of NF-κB. The QRT-treated group showed complete ulcer healing, with histological features almost like the control group, along with minimal collagen fiber deposition, decreased reactivity to CD86 and TNF-α and improvement of oxidative stress status and the molecular study results as well. CONCLUSION: QRT possess protective properties against CPT-11-triggered tongue injury.