Cyclic paroxysm and high fever are hallmarks of malaria and are associated with high levels of pyrogenic cytokines, including IL-1. In this report, we describe a signature for the expression of inflammasome-related genes and caspase-1 activation in malaria. Indeed, when we infected mice, Plasmodium infection was sufficient to promote MyD88-mediated caspase-1 activation, dependent on IFN--priming and the expression of inflammasome components ASC, P2X7R, NLRP3 and/or NLRP12. Pro-IL-1 expression required a second stimulation with LPS and was also dependent on IFN--priming and functional TNFR1. As a consequence of Plasmodium-induced caspase-1 activation, mice produced extremely high levels of IL-1 upon a second microbial stimulus, and became hypersensitive to septic shock. Therapeutic intervention with IL-1 receptor antagonist prevented bacterial-induced lethality in rodents. Similar to mice, we observed a significantly increased frequency of circulating CD14(+)CD16(-)Caspase-1(+) and CD14(dim)CD16(+)Caspase-1(+) monocytes in peripheral blood mononuclear cells from febrile malaria patients. These cells readily produced large amounts of IL-1 after stimulation with LPS. Furthermore, we observed the presence of inflammasome complexes in monocytes from malaria patients containing either NLRP3 or NLRP12 pyroptosomes. We conclude that NLRP12/NLRP3-dependent activation of caspase-1 is likely to be a key event in mediating systemic production of IL-1 and hypersensitivity to secondary bacterial infection during malaria. Author Summary Together Plasmodium falciparum and P. vivax infect approximately 250 million individuals, reaping life of near one million children every year. Extensive research on malaria pathogenesis has funneled into the consensus that the clinical manifestations are often a consequence of the systemic inflammation. Importantly, secondary bacterial and viral infections potentiate this inflammatory reaction being important co-factors for the development of severe disease. One of the hallmarks of malaria syndrome is the paroxysm, which is characterized by high fever associated with peak of parasitemia. In this study we dissected the mechanisms of induction and the importance of the pyrogenic cytokine, IL-1 in the pathogenesis of malaria. Our results demonstrate the critical role of the innate immune receptors named Toll-Like Receptors and inflammasome on induction, processing and release of active form of IL-1 during malaria. Importantly, we provide evidences that bacterial superinfection further potentiates the Plasmodium-induced systemic inflammation, leading to the release of bulk amounts of IL-1 and severe disease. Hence, this study uncovers new checkpoints that could be targeted for preventing systemic inflammation and severe malaria