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 22 counties in the eastern U.S. and various ecological and climatic factors. Babesiosis showed a negative relationship with mean annual temperature, while ehrlichiosis exhibited no clear associations with the investigated variables. Anaplasmosis prevalence was positively linked to nymphal tick densities, with the abundance of competent hosts mediating the relationship between prevalence and small mammal richness. Lyme disease prevalence was positively associated with densities of ticks and reservoir hosts, while negatively related with precipitation, temperature, and small mammal richness. In terms of effect size, the negative effect of temperature was the most important predictor for babesiosis, anaplasmosis and Lyme disease. We expand on previous works on the dilution effect in Lyme disease by linking reservoir hosts, tick density, and human cases at the regional scale. Our findings underscore the importance of ecological context in designing effective strategies for disease management, suggesting that TBD intervention efficacy may vary based on tick and host dynamics.