Intraventricular hemorrhage in preterm neonates has become a major global health problem and is associated with a high risk of post-hemorrhagic hydrocephalus (PHH). Identifying diagnostic markers and therapeutic targets is a focal challenge in the PHH prevention and control. Here, this study applies multi-omics analyses to characterize the biochemical, proteomic, and metabolomic profiles of the cerebrospinal fluid (CSF) in clinical human cohorts to investigate disease development and recovery processes occurring due to PHH. Integrative multiomics analysis suggests that the over-representation of ferroptosis, calcium, calcium ion binding, and cell adhesion signaling pathways is associated with PHH. Bioinformatic analysis indicates that chondroitin sulfate proteoglycan 4 (CSPG4) is discovered as a CSF biomarker and positively correlated with the ventricular size and the rate of periventricular leukomalacia. Next, it is further demonstrated that these signaling pathways are dysregulated in the choroid plexus (ChP) in PHH by using in vitro cellular experiments and rat models of PHH, whereas CSPG4 silencing can suppress ferroptosis, cell adhesion function, and the intracellular flow of Ca. These findings broaden the understanding of the pathophysiological mechanisms of PHH and suggest that CSPG4 may be an effective therapeutic target for PHH.