This study presents a quantification method for the assessment of the optic nerve head (ONH) deformations of the living human eye under acute intraocular pressure (IOP) elevation and change of cerebrospinal fluid pressure (CSFP) with body position. One eye from a brain-dead organ donor with open-angle glaucoma was imaged by optical coherence tomography angiography during an acute IOP and CSFP elevation test. Volumetric 3D strain was computed by digital volume correlation. With increase in IOP the shear strain consistently increased in both sitting and supine position (p < 0.001). When CSFP was increased at constant IOP by changing body position, a global reduction in the ONH strain was observed (−0.14% p = 0.0264). Strain in the vasculature was significantly higher than in the structural tissue (+0.90%, p = 0.0002). Retinal nerve fiber layer (RNFL) thickness strongly associated (ρ = −0.847, p = 0.008) with strain in the peripapillary sclera (ppScl) but not in the retina (p = 0.433) and lamina (p = 0.611). These initial results show that: CSFP independently to IOP modulates strain in the human ONH; ppScl strains are greater than strains in lamina and retina; strain in the retinal vasculature was higher than in the structural tissue; In this glaucoma eye, higher ppScl strain associated with lower RNFL thickness.