Tick-borne disease (TBD) incidences are rising globally, highlighting the need for effective prevention strategies that consider the ecological context of disease transmission. We analyzed the relationship between human prevalence of four TBDs in the eastern U.S. and various ecological and climatic factors. Babesiosis showed a negative relationship with mean annual temperature, while ehrlichiosis exhibited no significant associations. Anaplasmosis prevalence was positively linked to nymphal tick densities, with competent host abundance mediating the relationship between prevalence and small mammal richness. Lyme disease prevalence correlated positively with densities of ticks, infected ticks, deer, and reservoir hosts, while negatively correlating with precipitation, temperature, and small mammal richness. We expand on the dilution effect in Lyme disease by linking reservoir hosts, tick density, and human cases at broader scales. Our findings suggest that TBD intervention efficacy may vary based on tick and host dynamics, underscoring the importance of ecological context in designing effective strategies.