Currently, there is limited knowledge about socioeconomic, neighbourhood, and local ecological factors that contribute to the growing Lyme disease incidence in the province of Ontario, Canada. In this study, we sought to identify these factors that play an important role at the local scale, where people are encountering ticks in their communities. We used reported human Lyme disease case data and tick surveillance data submitted by the public from 2010–2017 to analyze trends in tick exposure, spatiotemporal clusters of infection using the spatial scan statistic and Local Moran’s I statistic, and socioecological risk factors for Lyme disease using a multivariable negative binomial regression model. Data were analyzed at the smallest geographic unit, consisting of 400–700 individuals, for which census data are disseminated in Canada. We found significant heterogeneity in tick exposure patterns based on location of residence, with 65.2% of Lyme disease patients from the city of Ottawa reporting tick exposures outside their health unit of residence, compared to 86.1%—98.1% of patients from other, largely rural, health units, reporting peri-domestic exposures. We detected eight spatiotemporal clusters of human Lyme disease incidence in eastern Ontario, overlapping with three clusters of Borrelia burgdorferi-infected ticks. When adjusting for population counts, Lyme disease case counts increased with larger numbers of Borrelia burgdorferi-infected ticks submitted by the public, higher proportion of treed landcover, lower neighbourhood walkability due to fewer intersections, dwellings, and points of interest, as well as with regions of higher residential instability and lower ethnic concentration (Relative Risk [RR] = 1.25, 1.02, 0.67–0.04, 1.34, and 0.57, respectively, p < .0001). Our study shows that there are regional differences in tick exposure patterns in eastern Ontario and that multiple socioecological factors contribute to Lyme disease risk in this region.