Malaria is the deadliest parasitic infectious disease, responsible for over 600,000 deaths annually. Despite eliciting immune responses to acute infection, the lack of durable immunity hinders the development of highly efficacious vaccines. This study aims to unravel the mechanisms governing malaria susceptibility, the generation and maintenance of Plasmodium falciparum-specific memory cells, and the impact of parasitic co-infections on the immune response, by employing a transcriptomics approach to analyze peripheral blood mononuclear cells (PBMCs) collected from children in Mali, West Africa, a country with hyperendemic seasonal malaria. To pinpoint host determinants of susceptibility during the development of acquired immunity, we examined PBMCs from Malian children who differ in susceptibility to clinical malaria. Blood samples were collected at the onset, peak, and conclusion of the malaria season from children aged 4-6 years. We characterized the immune cell composition and cytokine secretion for a subset of 20 children per timepoint (10 children with no symptomatic malaria age-matched to 10 children with >2 symptomatic malarial illnesses), and gene expression patterns for six children (three per cohort) per timepoint. We noted higher frequency of HLA-DR+ CD4 T cells in protected children during the peak of the malaria season and comparable levels cytokine secretion after stimulation with malaria schizonts across all three time points. Additionally, we observed differences in the expression of genes related to cell death and inflammation; in particular, inflammatory genes such as CXCL10 and STAT1 and apoptotic genes such as XAF1 were upregulated in susceptible children before the transmission season began. This suggests that differences in apoptotic and inflammatory gene expression patterns can predict susceptibility to clinical malaria. While P. falciparum is highly prevalent in Mali, it is crucial to recognize that this parasite does not exist in isolation. Mali exhibits a high prevalence of multiple infectious pathogens ranging from viruses to parasites. Notably, Schistosoma haematobium, with an infection prevalence reaching 50% in children before the age of 16, significantly contributes to the burden of infection diseases experienced by individuals in this area. To investigate the impact of a chronic S. haematobium infection on immune responses during acute P. falciparum infection and convalescence, we utilized single-cell RNA-sequencing on PBMCs from 20 Malian children. We successfully identified distinct subsets of T cells, B cells, natural killer (NK) cells, and myeloid cells. Notably, gene expression differences were observed due to the presence of a P. falciparum infection, while S. haematobium co-infection did not significantly impact gene expression. Additionally, we analyzed gene expression profiles in numerous CD4 T cell subsets and identified a unique cytotoxic CD4 T cell population. Differential expression analysis revealed increased expression of lymphocyte activation gene 3 (LAG3), basic leucine zipper ATF-like transcription factor (BATF), interferon, and interleukin 18 (IL18) receptor genes across distinct CD4 T cell populations during an acute malaria episode. Furthermore, we observed upregulation of the NR4A family of transcription factors in P. falciparum-negative, malaria-exposed children, suggesting their potential role in T cell dysfunction which may explain sub-optimal immunity observed during a secondary P. falciparum infection. This study provides valuable insights into immune responses in children exposed to P. falciparum and sheds light on potential regulatory networks involving BATF and NR4A family members. The dynamic gene expression patterns suggest a complex response to antigenic factors, highlighting the need for further research to understand the mechanisms shaping immune responses to infection and, particularly, co-infection.