Here, using CCl₄-induced liver injury models in mice and complementary in vitro cellular models, we found that MLKL deficiency reduced hepatocyte death and inflammatory responses in hepatic immune cells, thereby reducing collagen deposition and liver fibrosis. Mechanistically, MLKL deficiency attenuated hepatic inflammatory responses by reducing DAMPs release, preventing intracellular potassium depletion, and suppressing activation of the TLR–JNK signaling pathway.