Immunity that controls parasitemia and inflammation during Plasmodium falciparum (Pf) malaria can be acquired with repeated infections. A limited understanding of this complex immune response impedes the development of vaccines and adjunctive therapies. We conducted a prospective systems biology study of children who differed in their ability to control parasitemia and fever following Pf infection. By integrating whole-blood transcriptomics, flow-cytometric analysis, and plasma cytokine and antibody profiles, we demonstrate that a pre-infection signature of B cell enrichment, upregulation of T helper type 1 (Th1) and Th2 cell-associated pathways, including interferon responses, and p53 activation associated with control of malarial fever and coordinated with Pf-specific immunoglobulin G (IgG) and Fc receptor activation to control parasitemia. Our hypothesis-generating approach identified host molecules that may contribute to differential clinical outcomes during Pf infection. As a proof of concept, we have shown that enhanced p53 expression in monocytes attenuated Plasmodium-induced inflammation and predicted protection from fever. Display omitted •A 3-year study identifies children who control malaria fever and parasitemia•Systems analysis before and during infection in immune versus susceptible children•Cellular and humoral immune profiles associate with control of fever and parasitemia•p53 in monocytes attenuates malaria inflammation and predicts protection from fever The mechanisms that protect from febrile malaria remain unclear. Tran et al. applied a systems-based approach to a longitudinal pediatric study to identify immune signatures that associate with control of malaria fever and parasitemia, revealing that p53 upregulation in monocytes attenuates malaria-induced inflammation and predicts protection from fever.