Historical accounts suggest that malaria was endemic in ancient southern Anatolia, possibly as early as 800 BCE, but overwhelmingly from classical antiquity onwards. However, measuring the level and extent of malaria risk for premodern periods remains difficult, given the lack of quantifiable data. Surviving records indicate a particularly high prevalence of malaria-like symptoms in lowlands of Cilicia Pedias (southeastern Anatolia, modern Türkiye), especially with travellers for whom the region was a vital transit zone between Anatolia and Mesopotamia or the Levant. A geographic information system (GIS)-based multilayer malaria risk model developed for application to antiquity highlights the insalubrious nature of the region. For references to apparent malarial infection with spatial specificity, it provides quantified confirmation of malaria risk in the indicated locations. Combined with a new method for mapping ancient road paths, the model assigns risk figures to travel along those routes by merchants, pilgrims and armies throughout antiquity. Model-produced maps depict risk for Cilicia Pedias and its major roads. Modelled risk data correlate extremely well with historical accounts of malaria-like illness related to victims’ known itineraries from the 4th century BCE through the 12th century CE. These results support interpretation of reported sicknesses as malarial infection, and highlight the peril of the disease for immune-naïve travellers through the region; and, indeed, the impact of Plasmodium parasites on outcomes of certain historical events. This replicable model provides a case-study for combining GIS and text-based methodologies in evaluating malaria’s impact in the premodern Mediterranean, and application of similar techniques in other regions.