As a vector-borne disease, environmental determinants are a significant factor in the transmission of malaria to human populations throughout the world. The possibility of increased human-vector contact may occur in situations where alterations to the physical landscape result in a habitat favorable for the proliferation of the mosquito vector. Irrigation represents such environmentally-transformative actions capable of affecting the dynamics of malaria, particularly in regions where the disease is endemic. Here, over four decades of available data (1962-2008) from agricultural, healthcare, and population sources are incorporated into an analysis of the role of irrigation on nationwide malaria within those countries comprising the Amazon Forest region of South America for WHO strategy and prevention initiatives. Correlation and regression analyses reveal the presence of a relationship between changes in irrigated area and subsequent disease morbidity among eight of the nine nations of the region. With the exception of Ecuador, these results suggest that the totality of local scale alterations to the environment associated with irrigation development exert a significant influence upon the burden of malaria on the national level. Appreciating this relationship should be a cornerstone to planning and policy decisions involving water resource projects within these countries. The paper concludes with a discussion of other factors, such as migration and deforestation, whose potential to occur synergistically or concomitantly with irrigation produce a multifaceted challenge to effective disease management.