Ischemia-reperfusion (I/R) injury occurs during reperfusion after ischemia, worsening tissue damage. The Wnt signaling pathway, which interacts with multiple pathways like Notch, PI3K/Akt, TGF-β, NF-κB, BMP, NMDAR-Ca²⁺-Activin A, Hippo-YAP, TLR4/TRIF, and HGF/c-Met, plays a key role in I/R injury. The canonical Wnt pathway promotes organ recovery, while the non-canonical pathway exacerbates injury. This review explores the complex interactions between Wnt and other pathways in I/R injury, including apoptosis, inflammation, oxidative stress, ECM remodeling, angiogenesis, cell hypertrophy, fibrosis, ferroptosis, neurogenesis, and BBB damage. It also discusses therapeutic strategies targeting these pathways, based on animal studies, clinical trials, and current standards. The Wnt pathway is crucial in myocardial and cerebral I/R injury, with the canonical pathway promoting recovery and the non-canonical pathway causing damage. In myocardial I/R injury, Wnt/β-catenin signaling is inhibited, leading to apoptosis, while non-canonical pathways promote apoptosis through JNK activation or calcium overload. In cerebral I/R injury, Wnt signaling is inhibited, leading to apoptosis, ferroptosis, and inflammation. Targeting Wnt signaling or its upstream components can mitigate I/R injury by reversing the signaling pathways. Therapeutic approaches include modulating Wnt signaling, using exosomes, or targeting specific pathways like Wnt5a or sFRP-4. The review highlights the importance of understanding Wnt signaling in I/R injury to develop effective therapeutic strategies.Ischemia-reperfusion (I/R) injury occurs during reperfusion after ischemia, worsening tissue damage. The Wnt signaling pathway, which interacts with multiple pathways like Notch, PI3K/Akt, TGF-β, NF-κB, BMP, NMDAR-Ca²⁺-Activin A, Hippo-YAP, TLR4/TRIF, and HGF/c-Met, plays a key role in I/R injury. The canonical Wnt pathway promotes organ recovery, while the non-canonical pathway exacerbates injury. This review explores the complex interactions between Wnt and other pathways in I/R injury, including apoptosis, inflammation, oxidative stress, ECM remodeling, angiogenesis, cell hypertrophy, fibrosis, ferroptosis, neurogenesis, and BBB damage. It also discusses therapeutic strategies targeting these pathways, based on animal studies, clinical trials, and current standards. The Wnt pathway is crucial in myocardial and cerebral I/R injury, with the canonical pathway promoting recovery and the non-canonical pathway causing damage. In myocardial I/R injury, Wnt/β-catenin signaling is inhibited, leading to apoptosis, while non-canonical pathways promote apoptosis through JNK activation or calcium overload. In cerebral I/R injury, Wnt signaling is inhibited, leading to apoptosis, ferroptosis, and inflammation. Targeting Wnt signaling or its upstream components can mitigate I/R injury by reversing the signaling pathways. Therapeutic approaches include modulating Wnt signaling, using exosomes, or targeting specific pathways like Wnt5a or sFRP-4. The review highlights the importance of understanding Wnt signaling in I/R injury to develop effective therapeutic strategies.