Considerable interest in the relationship between biodiversity and disease has recently captured the attention of the research community, with important public policy implications. In particular, malaria in the Amazon region is often cited as an example of how forest conservation can improve public health outcomes. However, despite a growing body of literature and an increased understanding of the relationship between malaria and land use / land cover change (LULC) in Amazonia, contradictions have emerged. While some studies report that deforestation increases malaria risk, others claim the opposite. Assessing malaria risk requires examination of dynamic processes among three main components: (i) the environment (i.e. LULC and landscape transformations), (ii) vector biology (e.g. mosquito species distributions, vector activity and life cycle, plasmodium infection rates), and (iii) human populations (e.g. forest-related activity, host susceptibility, movement patterns). In this paper, we conduct a systematic literature review on malaria risk and deforestation in the Amazon focusing on these three components. We explore key features that are likely to generate these contrasting results using the reviewed articles and our own data from Brazil and Peru, and conclude with suggestions for productive avenues in future research. This article is part of the themed issue ‘Conservation, biodiversity and infectious disease: scientific evidence and policy implications'.