We demonstrate the possibilities and prospects of a new application of compression optical coherence elastography (C-OCE) for diagnosing precancerous lesions of the oral mucosa. C-OCE allows the study of nonlinear elasticity of bio-tissues and mapping of various elasticity parameters to differentiate individual morphological structures and pathologies in human tissues. This work demonstrates the first utilization of C-OCE to identify oral leukoplakia lesions in the palate and buccal mucosa using changes in epithelial stiffness caused by the development of hyperkeratosis, which leads to the appearance of a pronounced keratin layer on the surface of the lesions. C-OCE-based quantification of characteristic stiffness values makes it possible to differentiate various types of hyperkeratosis in proliferative verrucous leukoplakia lesions, such as orthohyperkeratosis and corrugated keratosis. Quantification of the dimensionless nonlinear elastic parameter
β
additionally enables differentiation of the keratin layer from the epithelial layer in proliferative verrucous leukoplakia lesions with corrugated keratosis. The first reported results obtained for excised tissue samples substantiate the prospects of C-OCE for the realization of new clinical tools for non-invasive diagnosis of oral pathologies.