Acute liver failure (ALF) is a rapidly progressing critical illness with a high mortality rate. Circulating inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), play a significant role in the pathophysiology of ALF through promoting hepatocellular apoptosis. Ginsenoside Rg1, the primary active ingredient in Panax ginseng (also termed Asian or Korean ginseng), has been reported to inhibit TNF-α production and has been shown to significantly attenuate liver fibrosis development. Here, we assessed ginsenoside Rg1’s potential as a therapy for ALF by investigating the effect of ginsenoside Rg1 treatment on circulating inflammatory markers, hepatocellular apoptosis, and relevant apoptotic signaling pathways in a well-established murine ALF model. We found that ginsenoside Rg1 significantly reduces liver damage in a murine ALF model through inhibiting TNF-α-induced, caspase-dependent hepatocellular apoptosis. These results support the further investigation of ginsenoside Rg1 as a therapeutic candidate for ALF.