Current understanding is that receptor interacting serine/threonine protein kinase 1 (RIPK1) can lead to two distinct forms of cell death: RIPK3-mediated necroptosis or caspase 8 (Casp8)-mediated apoptosis. Here, we report that RIPK1 signaling is indispensable for protection from hepatocellular injury in a steatotic liver undergoing ischemia reperfusion injury (IRI) but not in the lean liver. In lean liver IRI, RIPK1-mediated cell death is operational, leading to protection in RIP1 kinase-dead knock-in (RIPK1K45A) mice and necrostatin-1s (Nec1s)-treated lean wild-type (WT) mice. However, when fed a high-fat diet (HFD), RIPK1K45A-treated and Nec1s-treated WT mice undergoing IRI demonstrate exacerbated hepatocellular injury along with decreased RIPK1 ubiquitylation. Furthermore, we demonstrate that HFD-fed RIPK3-/-/Casp8-/- mice show protection from IRI, but HFD-fed RIPK3-/-/Casp8-/+ mice do not. We also show that blockade of RIPK1 leads to increased Casp8 activity and decreases mitochondrial viability. Conclusion: Although more studies are required, we provide important proof of concept for RIPK1 inhibition leading to distinctive outcomes in lean and steatotic liver undergoing IRI. Considering the rising incidence of nonalcoholic fatty liver disease (NAFLD) in the general population, it will be imperative to address this critical difference when treating patients with RIPK1 inhibitors. This study also presents a new target for drug therapy to prevent hepatocellular injury in NAFLD.