Impairment of the central nervous system (CNS) functions in astronauts is a major health risk for long-duration space missions. Here, for the first time, we combine single-cell multiomics (transcriptomics and chromatin accessibility) and spatial transcriptomics analyses to discover spaceflight-mediated changes in the mouse brain. By comparing ground control and spaceflight animals, we found that the main processes affected by spaceflight include neurogenesis, synaptogenesis and synaptic transmission in cortex, hippocampus, striatum and neuroendocrine structures as well as astrocyte activation and immune dysfunction. At the pathway level, spaceflight resembles neurodegenerative diseases with oxidative stress and protein misfolding components, such as in Parkinson’s disease. Our integrated spatial multiomics approach reveals both widespread and localized brain impairments and suggests key structures and mechanisms to be targeted for countermeasure development. All datasets can be mined through an interactive data portal as well as the National Aeronautics and Space Administration (NASA) GeneLab repositories.