A spectrum of ophthalmic abnormalities, including optic disc edema, globe flattening, chorioretinal folds, and hyperopic refractive error shifts, has been observed in astronauts during and after long-duration spaceflight. An increased understanding of factors contributing to this syndrome, initially termed “visual impairment and intracranial pressure syndrome” and recently renamed "Spaceflight Associated Neuro-Ocular Syndrome" (SANS), is currently a top priority for space agencies. At present, the exact mechanisms causing SANS are not completely understood. Elevated intracranial pressure and compartmentalization of cerebrospinal fluid within the orbital optic nerve sheath have been proposed as possible explanations for SANS. A novel potential mechanism of microgravity-induced optic disc edema pertains to the “ocular glymphatic system” concept and proposes that it may result, at least partly, from an imbalance of glymphatic fluid transport at the level of the optic nerve head. We propose that additional studies will play a critical role in understanding the contribution of the ocular glymphatic system in optic disc edema in SANS.