Convincing evidence has indicated that geniposide possesses neuroprotective effects in ischemic stroke. This study is designed to explore the potential molecular mechanism of geniposide in oxygen-glucose deprivation/reoxygenation (OGD/R)-treated BV-2 microglial cells and middle cerebral artery occlusion (MCAO) mice. OGD/R model in BV2 microglial cells was established in this research. Cell viability and apoptosis were determined using Cell Counting Kit-8 (CCK-8) and flow cytometry assays. Protein levels of B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), microtubule-associated protein light chain 3 (LC3)-II/LC3-I, Beclin-1, inducible nitric oxide synthase (iNOS), CD86, sex determining region Y-box 2 (SOX2), receptor-interacting serine/threonine-protein kinase 1 (RIPK1), TNF-α, IL-1β, ARG1, and CD163 were detected by western blot assay. RIPK1 mRNA level was determined using real-time quantitative polymerase chain reaction (RT-qPCR). TNF-α and IL-1β levels were analyzed using ELISA kits. After JASPAR analysis, binding between SOX2 and RIPK1 promoter was predicted and verified using chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays. The effects of geniposide on cerebral ischemic injury were assessed using MCAO mice in vivo. Geniposide treatment relieved OGD/R-triggered BV-2 cell viability promotion and apoptosis, autophagy, inflammatory response, and M1 polarization inhibition in vitro. SOX2 and RIPK1 expression was decreased in OGD/R-treated BV-2 cells. In mechanism, SOX2 upregulated RIPK1 transcription by binding to the RIPK1 promoter region. Geniposide administration significantly alleviated cerebral ischemic injury in MCAO mice in vivo. Geniposide administration protects against cerebral ischemic injury through regulating the SOX2/RIPK1 axis, providing a potential direction for the application of geniposide in the treatment of ischemic stroke.