As human populations expand into rural areas—increasing roadway usage and infrastructure—wildlife managers are challenged with conserving biodiversity while mitigating vehicle-animal conflicts. The Sonoran Desert ecoregion is rich for herpetofauna (i.e., amphibians and reptiles), yet sparse information exists about evening road usage by herpetofauna along rural roadways in the region. Acquiring baseline data and robust statistical testing can inform mitigation strategies in expanding communities. Through a multiyear road-cruising (i.e., vehicle-based surveys) project, we have generated quantitative data for when, where, and why herpetofauna use rural roads and which factors influence usage. Since 2018, we have conducted more than 135 systematic replicated post-sunset surveys (>3,000 km) from April–November across paved and unpaved road transects in rural and rural-urban intergrade areas around Tucson and Phoenix, Arizona. To-date, we have recorded more than 350 herpetofauna as well as 700 “incidental” vertebrates (e.g., birds and mammals) as they are also important as predators, prey, and ecosystem service providers. For each survey and observation, we record intrinsic and extrinsic data including activity, behavior, environmental conditions, and traffic. To better understand the factors influencing road usage each year, we conduct generalized linear models, means statistics, and association tests. This includes relationships between traffic and roadkill rates; herpetofauna road placement (i.e., where in the road surface they are found); and roadkill rates by taxonomic group. Southern Arizona has been in a decadal drought, and summer monsoonal trends (e.g., precipitation, humidity) appear important in predicting herpetofauna road usage. In 2018 and 2019, humidity played a significant role in finding more herpetofauna. This is logical given many species, especially amphibians, have life history strategies tied to the wet summer season. However, 2020 was exceptionally hot and dry with about 1/3 rain than 2018–2019 (2020 amphibian observations were 2/3 fewer than 2019); road surface temperature best predicted 2020 herpetofauna. Herpetofauna are found dead on roads (DOR) significantly more than other taxa. Moreover, we found significantly more inactive or DOR herpetofauna in the “tire span” placement on roads, as opposed to road center, shoulder, or edges—notably, some DOR’s were well outside the normal drive-path suggesting intentional swerving. Alarmingly albeit unsurprisingly, we find traffic volume increases equate to increased DOR rates, regardless of taxa. Our results comprise data in rural desert areas that may soon see increased urbanization and development. Further resolution into how environmental and anthropogenic variables affect animal road usage can inform effective conservation management and road infrastructure decisions. Our long-term design is applicable to taxa and regions beyond the desert Southwest.