Ischemic stroke is one of the main causes of death and disability. Circular RNAs (circRNAs) have received extensive attention in the pathogenesis of ischemic stroke. Here, we evaluated the role of circCDC14A in cerebral ischemia-reperfusion (CI/R) injury in vivo and in vitro. The expression of circCDC14A was significantly upregulated in the middle cerebral artery occlusion (MCAO) model and oxygen and glucose deprivation/reoxygenation (OGD/R)-treated HT22 cells. Knockdown of circCDC14A suppressed the cell viability reduction caused by OGD/R, as well as cell damage and apoptosis. Mechanistically, circCDC14A acted as a sponge for miR-23a-3p and promoted the expression of chemokine stromal-derived factor-1 (CXCL12) by negatively regulating miR-23a-3p. Rescue experiments further confirmed that miR-23a-3p inhibitor or circCDC14A-overexpression vectors blocked the beneficial effects of circCDC14A knockdown in OGD/R-induced HT22 cells. Moreover, knockdown of circCDC14A suppressed MCAO-induced cerebral infarction and neurological damage, as well as the brain tissue damage and neuronal apoptosis in vivo. Consistently, miR-23a-3p antagomir treatment abolished the cerebral protective effects of circCDC14A knockdown on MCAO mice. In conclusion, circCDC14A promoted CI/R injury by regulating the miR-23a-3p/CXCL12 axis, which suggested that circCDC14A may become a potential therapeutic target for CI/R injury.