1. There is still little emphasis within One Health on building linkages between human health, changes in biodiversity, and ecosystem perturbation. 2. We use the Great Plains, a system of substantial One Health concern, to illustrate a persistent data challenge through the lens of small mammals, parasitic vectors of disease, and long-term ecosystem change. 3. With progressive ecological change of grasslands through woody encroachment, we see that shifting plant communities cause a turnover in dominant rodent species, changes in the evolutionary complexity of host-vector relationships, a reduction in host species richness and an increase in carrying capacity of both hosts and vectors. 4. Knowledge of these progressive and accelerating dynamics are evident through novel data syntheses and collectively indicate heightened risk of emerging zoonotic disease throughout the region. 5. We call for One Health research that promotes novel digitized data linkages between specimen time-series held in biorepositories, long-term ecological research initiatives, and surveillance of pathogens.