Leptospirosis is a zoonosis with global public health impact, particularly in poor socio-economic settings in tropical regions. Transmitted through urine-contaminated water or soil from rodents, dogs, and livestock, leptospirosis causes over a million clinical cases annually. Risk factors include outdoor activities, livestock production, and substandard housing that foster high densities of animal reservoirs. This One Health study in southern Chile examined Leptospira serological evidence of exposure in people from urban slums, semi-rural settings, and farm settings, using the Extreme Gradient Boosting algorithm to identify key influencing factors. In urban slums, age, shrub terrain, distance to Leptospira-positive households, and neighborhood housing density were contributing factors. Human exposure in semi-rural communities was linked to environmental factors (trees, shrubs, and lower vegetation terrain) and animal variables (Leptospira-positive dogs and rodents and proximity to Leptospira-positive households). On farms, dog counts, animal Leptospira prevalence, and proximity to Leptospira-contaminated water samples were significant drivers. The study underscores that disease dynamics vary across landscapes, with distinct drivers in each community setting. This case study demonstrates how the integration of machine learning with comprehensive cross-sectional epidemiological and geospatial data provides valuable insights into leptospirosis eco-epidemiology. These insights are crucial for informing targeted public health strategies and generating hypotheses for future research.