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Abstract Background Hypoxia inducible factor‐1α (HIF‐1α) is a sensitive indicator of oxygen homeostasis, of which the expression elevates following hypoxia/ischemia. This study reveals the specific mechanisms underlying the effects of HIF‐1α on ischemic stroke (IS). Methods IS model was established using middle cerebral artery occlusion (MCAO)‐modeled male rats and oxygen glucose deprivation/reoxygenation (OGD/R)‐treated mice hippocampal cells HT22, followed by the silencing of HIF‐1α and the overexpression of C‐X‐C motif chemokine receptor 4 (CXCR4) and nuclear factor‐kappa B (NF‐κB). Following the surgery, Garcia's grading scale was applied for neurological evaluation. Cerebral infarcts and injuries were visualized using 2,3,5‐triphenyltetrazolium chloride and hematoxylin‐eosin staining. The levels of tumor necrosis factor‐α, Interleukin (IL)‐6, IL‐1β, malondialdehyde, and 8‐hydroxy‐2′‐deoxyguanosine, were calculated via ELISA. MTT assay and lactate dehydrogenase (LDH) assay kit were adopted to determine the viability and cytotoxicity of OGD/R‐modeled cells. Reactive oxygen species (ROS) generation was evaluated using a 2′‐7′dichlorofluorescin diacetate (DCFH‐DA) probe. The levels of HIF‐1α, CXCR4, and NF‐κB p65 were quantified via Western blot and immunofluorescence, respectively. Results HIF‐1α knockdown improved Garcia's score, attenuated the cerebral infarct, inflammation, and ROS generation, and alleviated the levels of inflammatory cytokines and CXCR4/NF‐κB p65 in MCAO‐modeled rats. Such effects were reversed following the overexpression of CXCR4 and NF‐κB. Also, in OGD/R‐treated HT22 cells, HIF‐1α silencing diminished the cytotoxicity and ROS production and reduced the expressions of CXCR4/NF‐κB p65, while promoting viability. However, CXCR4/NF‐κB p65 overexpression did the opposite. Conclusion HIF‐1α knockdown alleviates inflammation and oxidative stress in IS through the CXCR4/NF‐κB pathway.