The dynamics of zoonotic vector-borne diseases are determined by a complex set of parameters including human behavior that may vary with socio-ecological contexts. Lyme disease is the most common vector-borne disease in the United States. The Northeast and upper Midwest are the regions most affected - two areas with differing levels of urbanization and differing sociocultural settings. The probability of being infected with Lyme disease is related to the risk of encounters with Ixodes scapularis ticks infected with Borrelia burgdorferi sensu lato, which reflects both the environmental tick hazard and human behaviors. Herein, we compare behavioral and peridomestic risk factors perceived to influence the risk for human-tick encounters between two high-incidence states in the Northeast (New York and New Jersey) and one high-incidence state in the Midwest (Wisconsin). We used a smartphone application, The Tick App, as a novel survey tool, during spring and summer of 2018. Adaptive human behavior was identified in the relationship between outdoor activities and the use of methods to prevent tick bites. More frequent recreational outdoor activities and gardening (a peridomestic activity) were associated with a 1.4-2.3 times increased likelihood of using personal protective measures to prevent tick bites, when accounting for demographics and previous Lyme diagnosis. Most outdoor activities were more frequently reported by participants from the Midwest (n = 697), representing an older demographic, than the Northeast (n = 396). Participants from the Northeast were less likely to report use of personal protective measures to prevent tick bites, but a larger proportion of participants from the Northeast reported application of environmental pesticides targeting ticks or mosquitoes or other insects on their property (34 % of 279 versus 22 % of 616 participants) and interventions to reduce the presence of peridomestic deer compared to participants from the Midwest (e.g. 20 % of 278 versus 7% of 615 participants reported having a deer proof fence). Participants from the Midwest were more likely to kill rodents on their property (28 % versus 13 %). These differences illustrate the need for further assessment of personal behavior and tick exposure in these two Lyme disease-endemic regions to aid in targeted public health messaging to reduce tick-borne diseases.