Lyme disease is the most prevalent vector-borne disease in North America, and both the annual incidence and geographic range are increasing. The emergence of Lyme disease has been attributed to a century-long recovery of deer, an important reproductive host for adult ticks. However, a growing body of evidence suggests that Lyme disease risk may now be more dynamically linked to fluctuations in the abundance of small-mammal hosts that are thought to infect the majority of ticks. The continuing and rapid increase in Lyme disease over the past two decades, long after the recolonization of deer, suggests that other factors, including changes in the ecology of small-mammal hosts may be responsible for the continuing emergence of Lyme disease. We present a theoretical model that illustrates how reductions in small-mammal predators can sharply increase Lyme disease risk. We then show that increases in Lyme disease in the northeastern and midwestern United States over the past three decades are frequently uncorrelated with deer abundance and instead coincide with a range-wide decline of a key small-mammal predator, the red fox, likely due to expansion of coyote populations. Further, across four states we find poor spatial correlation between deer abundance and Lyme disease incidence, but coyote abundance and fox rarity effectively predict the spatial distribution of Lyme disease in New York. These results suggest that changes in predator communities may have cascading impacts that facilitate the emergence of zoonotic diseases, the vast majority of which rely on hosts that occupy low trophic levels.