Spaceflight-associated dry eye syndrome (SADES) has been reported among astronauts during both International Space Station (ISS) and Space Transportation System (STS) missions. As future missions extend beyond low Earth orbit, the physiological challenges of spaceflight include microgravity, radiation, and environmental stressors, which may further exacerbate the development of ocular surface disease. A deeper understanding of the underlying pathophysiology, along with the exploration of innovative countermeasures, is critical. In this review, we examine nanomedicine as a promising countermeasure for managing ophthalmic conditions in space, with the goal of enhancing visual health and mission readiness for long-duration exploration-class missions.