Sensorimotor functioning is adaptively altered following long-duration spaceflight. The question of whether microgravity affects other central nervous system functions such as brain network organization and its relationship with behavior is largely unknown, but of importance to the health and performance of astronauts both during and post-flight. In the present study, we investigate the effects of prolonged exposure to an established spaceflight analog on resting state brain functional connectivity and its association with behavioral changes in 17 male participants. These bed rest participants remained in bed with their heads tilted down six degrees below their feet for 70 consecutive days. Resting state functional magnetic resonance imaging (rs-fMRI) and behavioral data were obtained at seven time points averaging around: 12 and 8days prior to bed rest; 7, 50, and 70days during bed rest; and 8 and 12days after bed rest. To assess potential confounding effects due to scanning interval or task practice, we also acquired rs-fMRI and behavioral measurements from 14 control participants at four time points. 70days of head-down tilt (HDT) bed rest resulted in significant changes in the functional connectivity of motor, somatosensory, and vestibular areas of the brain. Moreover, several of these network alterations were significantly associated with changes in sensorimotor and spatial working memory performance, which suggests that neuroplasticity mechanisms may facilitate adaptation to the microgravity analog environment. The findings from this study provide novel insights into the underlying neural mechanisms and operational risks of spaceflight analog-related changes in sensorimotor performance.