Climate variability, particularly the frequency of extreme events, is likely to increase in the coming decades, with poorly understood consequences for terrestrial ecosystems. Hydroclimatic variations of the Medieval Climate Anomaly (MCA) provide a setting for studying ecological responses to recent climate variability at magnitudes and timescales comparable to expectations of coming centuries. We examined forest response to the MCA in the humid western Great Lakes region of North America, using proxy records of vegetation, fire, and hydroclimate. Multi-decadal moisture variability during the MCA was associated with a widespread, episodic decline in Fagus grandifolia (beech) populations. Spatial patterns of drought and forest changes were coherent, with beech declining only in areas where proxy-climate records indicate that severe MCA droughts occurred. The occurrence of widespread, drought-induced ecological changes in the Great Lakes region indicates that ecosystems in humid regions are vulnerable to rapid changes in drought magnitude and frequency.