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Background: Malaria epidemics are increasing in East Africa since the 1980s, coincident with rising temperature and widening climate variability. A projected 1–3.5 °C rise in average global temperatures by 2100 could exacerbate the epidemics by modifying disease transmission thresholds. Future malaria scenarios for the Lake Victoria Basin (LVB) are quantified for projected climate scenarios spanning 2006–2100. Methods: Regression relationships are established between historical (1995–2010) clinical malaria and anaemia cases and rainfall and temperature for four East African malaria hotspots. The vector autoregressive moving average processes model, VARMAX (p,q,s), is then used to forecast malaria and anaemia responses to rainfall and temperatures projected with an ensemble of eight General Circulation Models (GCMs) for climate change scenarios defined by three Representative Concentration Pathways (RCPs 2.6, 4.5 and 8.5). Results: Maximum temperatures in the long rainy (March–May) and dry (June–September) seasons will likely increase by over 2.0 °C by 2070, relative to 1971–2000, under RCPs 4.5 and 8.5. Minimum temperatures (June–September) will likely increase by over 1.5–3.0 °C under RCPs 2.6, 4.5 and 8.5. The short rains (OND) will likely increase more than the long rains (MAM) by the 2050s and 2070s under RCPs 4.5 and 8.5. Historical malaria cases are positively and linearly related to the 3–6-month running means of monthly rainfall and maximum temperature. Marked variation characterizes the patterns projected for each of the three scenarios across the eight General Circulation Models, reaffirming the importance of using an ensemble of models for projections. Conclusions: The short rains (OND), wet season (MAM) temperatures and clinical malaria cases will likely increase in the Lake Victoria Basin. Climate change adaptation and mitigation strategies, including malaria control interventions could reduce the projected epidemics and cases. Interventions should reduce emerging risks, human vulnerability and environmental suitability for malaria transmission. [ABSTRACT FROM AUTHOR]