With a combination of a cell-based high-throughput screening, brain slice electrophysiology, and in vivo genetic silencing in an experimental cerebral malaria (eCM) model, we discovered a TNFR1–FGF14–Nav1.6 signaling network mediated by JAK2 and demonstrated its regulatory effects at the cellular, circuital, and behavior levels. This evidence concerns the gene SCN8A and cerebral malaria.