Hypoxic-ischemic encephalopathy (HIE) is a detrimental factor in infant death and chronic disease. The specific pathogenesis is not entirely clear. Therefore, exploring the pathogenesis of HIE is critical. The expression of miR-19b-3p and SOX6 in umbilical blood of HIE patients was detected by qRT-PCR assay. HT22 cells were triggered with oxygen-glucose deprivation/reoxygenation (OGD/R) to construct the HIE cell model. Cell Counting Kit-8 (CCK-8) assay was used to estimate viability. SOD and MDA levels were detected by enzyme linked immunosorbent assay. Flow cytometry was implemented to ascertain neurocyte apoptosis. Cellular β-catenin immunofluorescence staining was used to detect the expression and distribution of β-catenin protein. Wnt signaling pathway activation was detected by TOPFlash/FOPFlash luciferase reporter assay. The targeting correlation of SOX6 and miR-19b-3p was corroborated by dual-luciferase reporter gene assay and RNA pull-down assay. MiR-19b-3p expression was once down-regulated, whilst SOX6 expression was up-regulated in HIE patients. MiR-19b-3p overexpression promoted cell proliferation, repressed cell apoptosis, oxidative stress response, and Wnt/β-catenin pathway activation in OGD/R-triggered HT22 cells. MiR-19b-3p negatively regulated SOX6 expression. SOX6 knockdown improved OGD/R-triggered HT22 cells injury via Wnt/β-catenin pathway activation. MiR-19b-3p overexpression suppressed OGD/R-triggered HT22 cell injury via inhibiting SOX6 expression via activating Wnt/β-catenin pathway.