Background <p>Regular physical activity (PA) confers numerous benefits to both peripheral and cerebral health, including enhanced cardiovascular and muscular function, as well as improved cognitive performance and neuroplasticity. The hippocampus, a brain region highly sensitive to the effects of PA, has been consistently shown to undergo structural enhancements with sustained exercise. However, the impact of physical detraining—the cessation or significant reduction of regular PA—on hippocampal structure remains largely unexplored, particularly in humans. This study aimed to investigate whether a 14-day period of voluntary exercise reduction leads to measurable structural changes in the hippocampus, and whether these changes are associated with anxiety symptomatology.</p> Results <p>Paired t-tests analyses did not reveal significant changes in hippocampal volume for the whole sample. However, multiple regression analyses on volume change including physical fitness index and degree of moderate and vigorous PA reduction as independent variables, revealed a significant decrease in hippocampal gray matter volume following detraining in individuals with greater MVPA reduction. Notably, pre and post-detraining state anxiety levels were lower in participants who showed larger reductions in hippocampal volume.</p> Conclusions <p>These findings suggest that even short-term interruptions in regular physical activity may prompt rapid structural changes in the hippocampus, modulated by the extent of detraining. The observed relationship between hippocampal volume reduction and decreased state anxiety points to stress regulation as a potential mechanism. Further research is warranted to explore the functional significance and potential reversibility of these neuroplastic changes.</p>