Background <p>Children with central nervous system malaria (CNS-M) have gene expression profiles and plasma biomarkers of malaria pathogenesis that differ from children with uncomplicated malaria (UM, malaria infection with fever and no systemic organ dysfunction) or acute febrile non-malaria illness (AFN). However, there is scant knowledge of the temporal dynamics of gene expression and plasma biomarkers during recovery from CNS-M.</p> Methods <p>We compared serial changes of peripheral blood mononuclear cell transcriptomes at 6 weeks after recovery and plasma biomarkers of malaria pathogenesis at 6 weeks and 6 months after recovery in cohorts of Kenyan children who presented with CNS-M (<i>n</i> = 37), UM (<i>n</i> = 20) and AFN (<i>n</i> = 12).</p> Results <p>Upregulated genes and Reactome pathways of interleukin/cytokine signaling, neutrophil degranulation and innate immunity and downregulated pathways of protein biosynthesis of children presenting with CNS-M were partially reversed at hospital discharge 2–6 days later and 6 weeks. CNS-M and UM transcriptomes before treatment versus 6 weeks after recovery shared several pathways, but megakaryocyte/platelet production, IL-4/IL-13/IL-10 signaling and overexpression of <i>LAG3</i>, <i>CCR5</i>, <i>PDGFRB</i> and <i>ICMT</i> were specific to CNS-M. The Hemostasis Reactome pathway was uniquely downregulated in CNS-M at 6 weeks. Biomarkers of coagulation, fibrinolysis, neutrophil activation, endothelium integrity and cytokine signaling correlated with high plasma cell-free DNA in acute CNS-M and persisted for 6 weeks, whereas these values normalized at 6 weeks in UM and AFN.</p> Conclusions <p>Recovery from pediatric CNS-M is associated with prolonged dysregulation of gene expression and biomarkers associated with coagulation, fibrinolysis and platelet activation. Future studies are needed to evaluate whether this dysregulation is associated with neurocognitive sequelae following recovery.</p> Clinical trial <p>Not applicable.</p>