Lyme disease (LD) is the most common tick-borne disease in North America. It is caused by Borrelia burgdorferi and transmitted to humans by blacklegged ticks, Ixodes scapularis. The life cycle of the LD vector, I. scapularis, usually takes two to three years to complete and goes through three stages, all of which are dependent on environmental factors. Increases in daily average temperatures, a manifestation of climate change, might have contributed to an increase in tick abundance via higher rates of tick survival. Additionally, these environmental changes might have contributed to better host availability, which is necessary for tick feeding and life cycle completion. In fact, it has been shown that both tick activity and survival depend on temperature and humidity. In this study, we have examined the relationship between those climatic variables and the reported incidence of LD in 15 states that contribute to more than 95% of reported cases within the Unites States. Using fixed effects analysis for a panel of 468 U.S. counties from those high-incidence states with annual data available for the period 2000–2016, we have found sizable impacts of temperature on the incidence of LD. Those impacts can be described approximately by an inverted U-shaped relationship, consistent with patterns of tick survival and host-seeking behavior. Assuming a 2°C increase in annual average temperature—in line with mid-century (2036–2065) projections from the latest U.S. National Climate Assessment (NCA4)—we have predicted that the number of LD cases in the United States will increase by over 20 percent in the coming decades. These findings may help improving preparedness and response by clinicians, public health professionals, and policy makers, as well as raising public awareness of the importance of being cautious when engaging in outdoor activities.