ABSTRACT Purpose To investigate the effect of globe and optic nerve (ON) morphologies and tissue stiffnesses on gaze-induced optic nerve head deformations using parametric finite element modeling and a Design of Experiment (DOE) approach. Methods A custom software was developed to generate finite element models of the eye using 10 morphological parameters: dural radius, scleral, choroidal, retinal, pial, peripapillary border tissue thicknesses, prelaminar tissue depth, lamina cribrosa (LC) depth, ON radius, and ON tortuosity. A 10-factor 2-level full-factorial analysis (1,024 models) was used to predict the effects of each morphological factor and their interactions on LC strains induced by 13° adduction. Subsequently, a further DOE analysis (1,024 models) was conducted to study the effects and potential interactions between the top 5 morphological parameters identified from the initial DOE study and 5 critical tissue stiffnesses. Results In the DOE analysis of 10 morphological parameters, the five most significant factors were ON tortuosity, dural radius, ON radius, scleral thickness and LC depth. Further DOE analysis incorporating biomechanical parameters highlighted the importance of dural and LC stiffness. A larger dural radius and stiffer dura increased LC strains but the other main factors had the opposite effects. Notably, a significant interaction was found between dural radius and dural stiffness. Conclusions This study highlights the significant impact of morphological factors on LC deformations during eye movements, with key morphological effects being more pronounced than tissue stiffnesses.