The cornea’s mechanical response to intraocular pressure elevations may alter in ectatic diseases such as keratoconus. Regional variations of mechanical deformation in normal and keratoconus eyes during intraocular pressure elevation have not been well-characterized. We applied a high-frequency ultrasound elastography technique to characterize the regional deformation of normal and keratoconus human corneas through the full thickness of corneal stroma. A cross-section centered at the corneal apex in 11 normal and 2 keratoconus human donor eyes was imaged with high-frequency ultrasound during whole globe inflation from 5 to 30 mmHg. An ultrasound speckle tracking algorithm was used to compute local tissue displacements. Radial, tangential, and shear strains were mapped across the imaged cross-section. Strains in the central (1 mm surrounding apex) and paracentral (1 to 4 mm from apex) regions were analyzed in both normal and keratoconus eyes. Additional regional analysis was performed in the eye with severe keratoconus presenting significant thinning and scarring. Our results showed that in normal corneas, the central region had significantly smaller tangential stretch than the paracentral region, and that within the central region, the magnitudes of radial and shear strains were significantly larger than that of tangential strain. The eye with mild keratoconus had similar shear strain but substantially larger radial strains than normal corneas, while the eye with severe keratoconus had similar overall strains as in normal eyes but marked regional heterogeneity and large strains in the cone region. These findings suggested regional variation of mechanical responses to intraocular pressure elevation in both normal and keratoconus corneas, and keratoconus appeared to be associated with mechanical weakening in the cone region, especially in resisting radial compression. Comprehensive characterization of radial, tangential, and shear strains through corneal stroma may provide new insights to understand the biomechanical alterations in keratoconus.