Research on the influence of the surrounding environment on Lyme disease has previously focused on the two major foci of Lyme disease reported cases in the Northeastern and Upper Midwestern regions of the United States, but there is a lack of understanding of Lyme disease in emerging areas. This study focuses on the influence of land use and climate factors on the counties of Illinois and the counties of neighboring states using the total reported Lyme disease cases from 2000 to 2017 by the Center for Disease Control and Prevention. Variables representing the percent of forest habitat, human development, and open water were obtained from the national land cover database from 2011. Average annual temperature and average annual precipitation from 2000 to 2017 were calculated from the National Climatic Data Center’s nClimDiv dataset. A negative binomial model was used to analyze the relationship between Lyme disease and the environmental variables. The final model estimates were used to establish maps visualizing how land use and climate are influencing the spatial distribution of Lyme disease across the study region.