This study aimed at understanding how landscape heterogeneity influences outbreaks of contagious diseases in southern Africa. Landscape attributes influence patterns of movement and behaviour of animal hosts, virus spread and survival, as well as land use practices. A multi-agent simulation was developed to represent the spatial and temporal dynamics of pathogens between human-livestock and wildlife interfaces at the fringe of large wildlife conservation areas. The model represents the three main elements associated with epidemics – populations, space, and time – to simulate direct contacts between wildlife and livestock. The dynamics of these populations emerge from interactions between agents and the landscape. The model was calibrated to represent the transmission of foot-and-mouth disease through direct contact at the border of the Kruger National Park in South Africa. In the region, African buffaloes (Syncerus caffer) act as reservoirs of the virus and spread the infection to domestic cattle bordering the park. We tested the sensitivity of various factors influencing contact rate between buffaloes and cattle, and thus the risk of foot-and-mouth disease transmission. Results show that cattle–buffalo contacts mostly depend on the range of displacements of cattle and buffaloes, as influenced by the landscape configuration, and on the number of fence breakages multiplied by the time between breakage and repair. Contacts take place not only close to water-points but also in grazing areas, within an area up to 6 km from the fence.