AbstractCardiovascular exercise (CE) is an evidence-based healthy lifestyle strategy. Yet, little is known about its effects on brain and cognition in young adults. Furthermore, evidence supporting a causal path linking CE to human cognitive performance via neuroplasticity is currently lacking. To understand the brain networks that mediate the CE–cognition relationship, we conducted a longitudinal, controlled trial with healthy human participants to compare the effects of a 2–week CE intervention against a non-CE control group on cognitive performance. Concomitantly, we used structural and functional magnetic resonance imaging to investigate the neural mechanisms mediating between CE and cognition. On the behavioral level, we found that CE improved sustained attention, but not processing speed or short-term memory. Using graph theoretical measures and statistical mediation analysis, we found that a localized increase in eigenvector centrality in the left middle frontal gyrus, probably reflecting changes within an attention-related network, conveyed the effect of CE on cognition. Finally, we found CE-induced changes in white matter microstructure that correlated with intrinsic connectivity changes (intermodal correlation). These results suggest that CE is a promising intervention strategy to improve sustained attention via brain plasticity in young, healthy adults.