Oral squamous cell carcinoma (OSCC) is the most common form of head and neck cancer, and oxidative damage is associated with the development of OSCCs. Antioxidants have therefore been proposed for use as chemoprotective agents against different types of cancer. In the present study, the effect of the antioxidant quercetin, administered at doses of 10 and 100 mg/kg/day, was investigated in an experimental murine model of 4-nitroquinoline 1-oxide (4-NQO)-induced carcinogenesis. The survival of the treated animals, the plasmatic levels of reduced glutathione and the type and severity of lesions (according the International Histological Classification of Tumors and Bryne's Multifactorial Grading System for the Invasive Tumor Front) were assessed. Additionally, the organization of the extracellular matrix was analyzed by carbohydrate and collagen histochemistry, and immunohistochemistry was used to assess the expression of the tumor markers proliferating cell nuclear antigen and mutated p53. The results indicate that, despite the promising effect of quercetin in other studies, this drug is ineffective as a chemoprotective agent against 4-NQO-induced OSCC in mice at the assayed doses.