Malaria causes significant morbidity and mortality worldwide, disproportionately impacting parts of Africa. Disease phenotypes associated with malarial infection can vary widely, from subclinical to life-threatening. To date, prevention efforts, particularly those related to vaccine development, have been hindered by an incomplete understanding of which factors impact host immune responses resulting in these divergent outcomes. We applied single-cell RNA- sequencing to compare the immunological phenotypes of peripheral blood mononuclear cells (PBMCs) isolated from children with clinical and subclinical malarial infections in an area of high malaria transmission in northern Ghana. On average, clinical pediatric malaria infections were characterized by a higher fractional abundance of monocytes and an upregulation of innate immune responses, including those to type I and type II interferons and tumor necrosis factor-alpha (TNF-α) signaling via NFκB. Further, in the clinical malaria group, we identified more putative interactions between antigen-presenting cells and proliferating CD4 T cells and naïve CD8 T cells driven by MHC-I and MHC-II signaling pathways, respectively. Together, these findings highlight transcriptional differences between immune cell subsets associated with disease phenotypes that may help guide the development of improved malaria vaccines and new therapeutic interventions for individuals residing in endemic areas.