Primary open angle Glaucoma (POAG) is one of the most common causes of permanent blindness in the world. Recent studies have suggested the hypothesis that POAG is also a central nervous system disorder which may result in additional (i.e., extra-ocular) involvement. The aim of this study is to assess possible structural, whole-brain connectivity alterations in POAG patients. We evaluated 23 POAG patients and 15 healthy controls by combining multi-shell diffusion weighted imaging, multi-shell, multi-tissue probabilistic tractography, graph theoretical measures and a recently designed ‘disruption index’, which evaluates the global reorganization of brain networks. We also studied the associations between the whole-brain structural connectivity measures and indices of visual acuity including the field index (VFI) and two Optical Coherence Tomography (OCT) parameters, namely the Macula Ganglion Cell Layer (MaculaGCL) and Retinal Nerve Fiber Layer (RNFL) thicknesses. We found both global and local structural connectivity differences between POAG patients and controls, which extended well beyond the primary visual pathway and were localized in the left calcarine gyrus (clustering coefficient p = 0.036), left lateral occipital cortex (clustering coefficient p = 0.017, local efficiency p = 0.035), right lingual gyrus (clustering coefficient p = 0.009), and right paracentral lobule (clustering coefficient p = 0.009, local efficiency p = 0.018). Group-wise (clustering coefficient, p=6.59∙10 7 and local efficiency p=6.23 10-8) and subject-wise disruption indices (clustering coefficient, p=0.018 and local efficiency, p=0.01) also differed between POAG patients and controls. In addition, we found negative associations between RNFL thickness and local measures (clustering coefficient, local efficiency and strength) in the right amygdala (local efficiency p=0.008, local strength p=0.016), right inferior temporal gyrus (clustering coefficient p=0.036, local efficiency p=0.042), and right temporal pole (local strength p=0.008). Overall, we show, in patients with POAG, a whole-brain structural reorganization that spans across a variety of brain regions involved in visual processing, motor control, and emotional/cognitive functions. We also identified a pattern of brain structural changes in relation to POAG clinical severity. Taken together, our findings support the hypothesis that the reduction in visual acuity from POAG can be driven by a combination of local (i.e., in the eye) and more extended (i.e., brain) effects.