Several models of tumor necrosis factor (TNF)/TNF‐receptor 1 (TNF‐R1)‐dependent liver injury in mice were investigated with respect to caspase‐3–like protease activation representing a pivotal mechanism of apoptotic cell death. Injection of TNF or T‐cell–activating agents (i.e., agonistic anti‐CD3 antibody or staphylococcal enterotoxin B [SEB]) into galactosamine (GalN)‐sensitized mice caused TNF/TNF‐R1–dependent liver injury. Intravenous concanavalin A (Con A) alone induced TNF‐mediated hepatotoxicity dependent on both TNF‐R1 and TNF‐R2. Hepatic caspase‐3–like proteases were activated in GalN/TNF, GalN/anti‐CD3, or GalN/SEB‐treated mice, but not in Con A–treated mice. Consistently, the broad‐spectrum caspase inhibitor, benzoyloxycarbonyl‐val‐ala‐asp‐fluoromethylketone (zVADfmk), prevented TNF‐mediated hepatotoxicity in all GalN‐dependent models, but failed to protect against Con A. Under transcriptional arrest, however, Con A induced TNF‐R1–dependent, but not TNF‐R2–dependent, activation of caspase‐3–like proteases, and zVADfmk prevented animals from Con A–mediated liver injury under this condition. Histological analysis revealed distinct differences between Con A– and GalN/Con A–induced liver injury regarding apoptotic morphology of hepatocytes. We conclude that impaired transcription induces a switch of Con A hepatotoxicity toward a caspase‐3–like protease‐dependent pathway. The observation that the functional state of the transcriptional machinery decides whether TNF‐driven hepatocyte apoptosis involves activation of caspase‐3–like proteases or alternative signaling pathways in vivo might be of relevance for the immunopathology of the liver.