Liver ischemia and reperfusion injury (IRI) is a major cause of liver transplant failure. Such injuries involve many inflammatory processes and activate liver macrophages. Activation of the Notch1 protein and the Notch pathway modulate inflammatory responses, but the exact molecular mechanisms at play are not yet understood. To narrow this gap, a recent study investigated macrophage Notch1 in a mouse model of liver IRI. Liver ischemia and reperfusion activated the Notch1 protein in liver macrophages, and knocking out the Notch1 gene from macrophage precursors worsened the damage and increased inflammation. Macrophage Notch1 deficiency also inhibited the expression of β-catenin. This led to a TAK1-mediated inflammatory response and RIK3-mediated hepatocyte necroptosis, a type of inflammatory cell rupture. Restoring Notch1 to macrophages using lentivirus alleviated the liver damage in this knockout model and reduced some of the inflammatory response. While research in humans is needed, this study demonstrated that the macrophage Notch1-β-catenin axis is a key regulatory mechanism in liver IRI and that this axis may be a therapeutic target to manage organ IRI for transplant recipients.