Although human adaptation to spaceflight has been studied for decades, little is known about its long-term effects on brain and behavior. The present study investigated visuospatial performance and associated electrophysiological responses in astronauts before, during, and after an approximately half-year long mission to the International Space Station. Here we report findings demonstrating that cognitive performance can suffer marked decrements during spaceflight. Astronauts were slower and more error-prone on orbit than on Earth, while event-related brain potentials reflected diminished attentional resources. Our study is the first to provide evidence for impaired performance during both the initial (~ 8 days) and later (~ 50 days) stages of spaceflight, without any signs of adaptation. Results indicate restricted adaptability to spaceflight conditions and calls for new research prior to deep space explorations.