Malaria is caused by infection with Plasmodium parasites, which are spread by Anopheles mosquitoes. In 2022, there were over 600,000 malaria deaths, most in children younger than five-years-old in Sub-Saharan Africa. Despite a reduction in cases due to antimalarial drugs, vaccines and vector control, disruptions to prevention programs during the COVID-19 pandemic, drug resistance, and climate change challenge eradication and highlight the need for additional research. Interactions between humans and Plasmodium parasites during infection influence long-lasting immunity to the parasites but remain incompletely understood and difficult to study. Because the blood stage of the Plasmodium developmental cycle is critical for development of malaria symptoms and the target of many vaccines and treatments, analyses of host and parasite gene expression from human blood samples during infection using RNA-sequencing provide unique insights into host-pathogen interactions during symptomatic infection. Interpretation of these analyses is challenged by the presence of multiple immune cells and parasite developmental stages in the blood, concurrently, with unique gene expression signatures. I first adapted a gene expression deconvolution technique to estimate the proportion of each P. falciparum blood stage from bulk RNA-sequencing mixtures. Using dual RNA-sequencing of P. falciparum-infected blood samples from 136 children, I investigated how gene expression was associated with clinical parameters and how these patterns were influenced by the sample cell composition to better understand variations in the antimalarial immune response. I found that the parasitemia and the child’s age during infection were the main drivers of gene expression differences between children. Additionally, I investigated how gene expression varies with transmission using dual RNA-sequencing of 52 samples collected at different times during the malaria season to understand how the antimalarial immune response changes with parasite exposure. I found that human gene expression changes more during the malaria season than during periods of non-exposure, suggesting development of antimalarial immunity with transmission and stability of this response between seasons. Altogether, my findings improve our understanding of antimalarial immune responses as they vary between individuals and provide insight into potential mechanisms of the development of antimalarial immunity that can be exploited to improve treatment and prevention strategies.