Ischemia-reperfusion (I/R) injury occurs during reperfusion following ischemia, exacerbating initial tissue damage. The complex mechanisms underlying I/R injury, particularly the role of the Wnt signaling pathway, are not fully understood, hindering the development of effective therapeutic interventions. This review highlights the intricate interplay between the Wnt signaling pathway and other signaling pathways, including Notch, PI3K/Akt, TGF-β, NF-κB, BMP, NMDAR-Ca²⁺-Activin A, YAP, TLR4/Trif, and HGF/c-Met. The Wnt pathway interacts with these pathways to regulate key pathological processes such as apoptosis, inflammation, oxidative stress, ECM remodeling, angiogenesis, cell hypertrophy, fibrosis, ferroptosis, neurogenesis, and blood-brain barrier (BBB) damage during I/R injury. The activation of the canonical Wnt/β-catenin pathway promotes organ recovery, while the activation of non-canonical Wnt pathways exacerbates injury. The review also explores novel therapeutic approaches based on these findings, incorporating evidence from animal experiments, clinical trials, and current standards. The goal is to provide deeper insights into the roles of Wnt and its crosstalk signaling pathways in I/R-mediated processes and organ dysfunction, facilitating the development of innovative therapeutic agents for I/R injury.Ischemia-reperfusion (I/R) injury occurs during reperfusion following ischemia, exacerbating initial tissue damage. The complex mechanisms underlying I/R injury, particularly the role of the Wnt signaling pathway, are not fully understood, hindering the development of effective therapeutic interventions. This review highlights the intricate interplay between the Wnt signaling pathway and other signaling pathways, including Notch, PI3K/Akt, TGF-β, NF-κB, BMP, NMDAR-Ca²⁺-Activin A, YAP, TLR4/Trif, and HGF/c-Met. The Wnt pathway interacts with these pathways to regulate key pathological processes such as apoptosis, inflammation, oxidative stress, ECM remodeling, angiogenesis, cell hypertrophy, fibrosis, ferroptosis, neurogenesis, and blood-brain barrier (BBB) damage during I/R injury. The activation of the canonical Wnt/β-catenin pathway promotes organ recovery, while the activation of non-canonical Wnt pathways exacerbates injury. The review also explores novel therapeutic approaches based on these findings, incorporating evidence from animal experiments, clinical trials, and current standards. The goal is to provide deeper insights into the roles of Wnt and its crosstalk signaling pathways in I/R-mediated processes and organ dysfunction, facilitating the development of innovative therapeutic agents for I/R injury.