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Cerebral malaria (CM), the most lethal complication of Plasmodium falciparum severe malaria (SM), remains fatal for 15–25% of affected children despite the availability of treatment. P. falciparum infects and multiplies in erythrocytes, contributing to anemia, parasite sequestration, and inflammation. An unbiased proteomic assessment of infected erythrocytes and plasma samples from 24 Beninese children was performed to study the complex mechanisms underlying CM. A significant down-regulation of proteins from the ubiquitin–proteasome pathway and an up-regulation of the erythroid precursor marker transferrin receptor protein 1 (TFRC) were associated with infected erythrocytes from CM patients. At the plasma level, the samples clustered according to clinical presentation. Significantly, increased levels of the 20S proteasome components were associated with SM. Targeted quantification assays confirmed these findings on a larger cohort (n = 340). These findings suggest that parasites causing CM preferentially infect reticulocytes or erythroblasts and alter their maturation. Importantly, the host plasma proteome serves as a specific signature of SM and presents a remarkable opportunity for developing innovative diagnostic and prognostic biomarkers. Synopsis: A mass spectrometry-based proteomic screening of both plasma and infected erythrocytes from Beninese children with various clinical manifestations of malaria (Uncomplicated Malaria (UM), Severe Malarial Anemia (SMA), and Cerebral Malaria (CM)) was performed. An increase of TFRC abundance was observed in infected erythrocyte samples from CM patients when compared to UM patients, coupled with a decrease of plasmatic Transferrin levels. 20S proteasome abundance was increased in plasma from children with severe malaria (CM and SMA) compared to UM, suggesting that it could serve as potential biomarker of severe malaria. A deregulated iron metabolism pathway and an increased hemolytic anemia were described in the severe malaria groups. Six P. falciparum proteins involved in red blood cell invasion were quantified specifically in plasma samples from severe malaria cases. A mass spectrometry-based proteomic screening of both plasma and infected erythrocytes from Beninese children with various clinical manifestations of malaria (Uncomplicated malaria (UM), Severe Malarial Anemia (SMA), and Cerebral Malaria (CM)) was performed. [ABSTRACT FROM AUTHOR]