A better understanding of the relationship between the El Niño Southern Oscillation (ENSO), the climatic anomalies it engenders, and malaria epidemics could help mitigate the world-wide increase in incidence of this mosquito-transmitted disease. The purpose of this paper is to assess the possibility of using ENSO forecasts for improving malaria control. This paper analyses the relationship between ENSO events and malaria epidemics in a number of South American countries (Colombia, Ecuador, French Guiana, Guyana, Peru, Suriname, and Venezuela). A statistically significant relationship was found between El Niño and malaria epidemics in Colombia, Guyana, Peru, and Venezuela. We demonstrate that flooding engenders malaria epidemics in the dry coastal region of northern Peru, while droughts favor the development of epidemics in Colombia and Guyana, and epidemics lag a drought by 1 year in Venezuela. In Brazil, French Guiana, and Ecuador, where we did not detect an ENSO/malaria signal, non-climatic factors such as insecticide sprayings, variation in availability of anti-malaria drugs, and population migration are likely to play a stronger role in malaria epidemics than ENSO-generated climatic anomalies. In some South American countries, El Niño forecasts show strong potential for informing public health efforts to control malaria.