Activation of antiapoptotic signaling cascades, such as the reperfusion injury salvage kinase (RISK) and survivor activating factor enhancement (SAFE) pathways, is protective in a variety of tissues in the context of ischemia-reperfusion (IR) injury. Hepatic IR injury causes clinically significant hepatocellular damage in surgical procedures, including liver transplantation and hepatic resection, increasing associated morbidity and mortality. We previously found that the cardiovascular-expressed K+ voltage-gated channel ancillary subunit KCNE4 sex specifically influences the cardiac RISK/SAFE pathway response to IR and that Kcne4 deletion testosterone dependently exacerbates cardiac IR injury. Here, we discovered that germline Kcne4 deletion exacerbates hepatic IR injury damage in 13-mo-old male mice, despite a lack of Kcne4 expression in male mouse liver. Examining RISK/SAFE pathway induction, we found that Kcne4 deletion prevents the hepatic ERK1/2 phosphorylation response to IR injury. Conversely, in 13-mo-old female mice, Kcne4 deletion increased both baseline and post-IR GSK-3β inhibitory phosphorylation, and pharmacological GSK-3β inhibition was hepatoprotective. Finally, castration of male mice restored normal hepatic RISK/SAFE pathway responses in Kcne4-/- mice, eliminated Kcne4 deletion-dependent serum alanine aminotransferase elevation, and genotype independently augmented the hepatic post-IR GSK-3β phosphorylation response. These findings support a role for KCNE4 as a systemic modulator of IR injury response and uncover hormonally influenced, sex-specific, KCNE4-dependent and -independent RISK/SAFE pathway induction.