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The severity and timing of seasonal malaria epidemics is strongly linked with temperature and rainfall. Advance warning of meteorological conditions from seasonal climate models can therefore potentially anticipate unusually strong epidemic events, building resilience and adapting to possible changes in the frequency of such events. Here we present validation of a process-based, dynamic malaria model driven by hindcasts from a state-of-the-art seasonal climate model from the European Centre for Medium-Range Weather Forecasts. We validate the climate and malaria models against observed meteorological and incidence data for Botswana over the period 1982–2006; the longest record of observed incidence data which has been used to validate a modeling system of this kind. We consider the impact of climate model biases, the relationship between climate and epidemiological predictability and the potential for skillful malaria forecasts. Forecast skill is demonstrated for upper tercile malaria incidence for the Botswana malaria season (January–May), using forecasts issued at the start of November; the forecast system anticipates six out of the seven upper tercile malaria seasons in the observational period. The length of the validation time series gives confidence in the conclusion that it is possible to make reliable forecasts of seasonal malaria risk, forming a key part of a health early warning system for Botswana and contributing to efforts to adapt to climate change.