Hepatic ischemia/reperfusion (I/R) is a major adverse reaction to liver transplantation, hemorrhagic shock, or resection. Recently, the anti‐inflammatory properties of the axonal guidance cue netrin‐1 were reported. Here, we demonstrate that netrin‐1 also impacts the resolution of inflammation and promotes hepatic repair and regeneration during liver I/R injury. In initial studies, we investigated the induction of netrin‐1 and its receptors in murine liver tissues after I/R injury. Hepatic I/R injury was performed in mice with a partial genetic netrin‐1 deficiency (Ntn1^+/−) or wild‐type C57BL/6 treated with exogenous netrin‐1 to examine the endogenous and therapeutically administered impact of netrin‐1. These investigations were corroborated by studies determining the characteristics of intravascular leukocyte flow, clearance of apoptotic neutrophils (polymorphonuclear cells [PMNs]), production of specialized proresolving lipid mediators (SPMs), generation of specific growth factors contributing to the resolution of inflammation, and liver repair. Hepatic I/R was associated with a significant reduction of netrin‐1 transcript and protein in murine liver tissue. Subsequent studies in netrin‐1‐deficient mice revealed lower efficacies in reducing PMN infiltration, proinflammatory cytokine levels, and hepatic‐specific injury enzymes. Conversely, mice treated with exogenous netrin‐1 exhibited increased liver protection and repair, reducing neutrophil influx into the injury site, decreasing proinflammatory mediators, increasing efferocytosis of apoptotic PMNs, and stimulating local endogenous biosynthesis of SPMs and the generation of specific growth factors. Finally, genetic studies implicated the A2B adenosine receptor in netrin‐1‐mediated protection during hepatic I/R injury. Conclusion: The present study indicates a previously unrecognized role for netrin‐1 in liver protection and its contribution to tissue homeostasis and regeneration. (Hepatology 2016;63:1689‐1705)