PURPOSE. To measure the deformation of the human optic nerve head (ONH) and peripapillary tissue (PPT) in response to acute intraocular pressure (IOP) elevation. METHODS. The ONH and PPT of 14 human donor globes were imaged with high-frequency ultrasonography during inflation testing from 5 to 30 mm Hg. A correlation-based speckle tracking algorithm was used to compute tissue displacements, and the through-thickness, in- plane, and shear strains were calculated by using least-squares strain estimation methods. The ONH and PPT were segmented along the anterior-posterior direction and the nasal-temporal direction. Regional displacements and strains were analyzed and compared. RESULTS. The ONH displaced more posteriorly than the PPT in response to an acute IOP increase. Scleral canal expansion was minimal but correlated with ONH posterior displacement at all IOP levels. Through-thickness compression was concentrated in the anterior of both the ONH and the PPT. Shear was concentrated in the vicinity of the canal with higher shear in the peripheral ONH than the central ONH and higher shear in the PPT near the scleral canal than that further away from the canal. CONCLUSIONS. High-resolution ultrasound speckle tracking showed a displacement mismatch between the ONH and the PPT, larger compressive strains in the direction of IOP loading in the anterior ONH and PPT, and higher shear strains in the periphery of ONH in response to acute IOP elevation in the human eye. These findings delineate the deformation patterns within and around the ONH and may help understand IOP-associated optic nerve damage.