The choroid plexus (ChP) secretes a half-liter/day of cerebrospinal fluid (CSF) and is the blood-CSF barrier with critical immune functions. Hydrocephalus, commonly caused by infection or hemorrhage, lacks non-surgical treatments due to obscure pathobiology. We hypothesize that in acquired hydrocephalus, the dual ChP functions of CSF secretion and blood-CSF barrier maintenance become pathologically entangled in a maladaptive disease state. To test this hypothesis, we created novel rat models of post-infectious (PIH) and posthemorrhagic hydrocephalus (PHH) and conducted a multi-omics investigation of these animals to dissect the cellular, molecular, and physiological pathology underlying PIH and PHH. Our systems approach combined functional genomics to characterize the ChP immune response, including the first-ever single-cell transcriptomic profile of the ChP in a pathological condition, as well as in vivo assessments of ChP secretory capacity and CSF dynamics to systematically characterize fluid homeostasis. Integrated multi-omic analysis of diverse post-infectious (PIH) and post-hemorrhagic (PHH) hydrocephalus models show lipopolysaccharide and blood products, respectively, trigger highly similar Tlr4-dependent immune-secretory responses at the ChP-CSF interface. Activated ChP macrophages elicit a CSF “cytokine storm” that stimulates CSF production from ChP epithelial cells via a kinase-regulated multi-ion transporter protein complex. Genetic or pharmacological immunomodulation prevents acute PIH and PHH by antagonizing ChP-mediated CSF hypersecretion. These data expand our understanding of ChP immune-epithelial cell crosstalk, reframe PIH and PHH as related neuroinflammatory disorders, and identify a druggable target of ChP immune-secretory function.