<p>Acute liver failure (ALF) and acute-on-chronic liver failure (ACLF) are characterized by high mortality rates. A growing body of evidence highlights mitochondrial dysregulation as a central pathogenic driver in these diseases. We provide a detailed examination of mitochondrial structure and core physiological functions in hepatic homeostasis, including mitochondrial DNA (mtDNA) replication, adenosine triphosphate (ATP) generation, reactive oxygen species (ROS) homeostasis, cell apoptosis, calcium homeostasis, mitophagy and mitochondrial biogenesis. We further elaborate on the key mechanisms underlying mitochondrial dysfunction in liver failure, including mitochondrial structural dysfunction, mtDNA damage, energy metabolism disruption, oxidative stress imbalance, inflammatory response dysregulation, cell apoptosis dysregulation, calcium homeostasis imbalance and autophagy dysregulation. These pathological processes are triggered or exacerbated by multiple factors, including genetic defects, drugs/toxins, and viral/bacterial infections. Recognizing the pivotal role of mitochondria, we summarize promising therapeutic interventions that have emerged, encompassing mitochondrial protection, mitochondrial restoration and mitochondrial replacement. Finally, we outline critical unresolved gaps in the field, such as the determinants of hepatocyte mitochondrial selective vulnerability, validated mitochondrial-specific biomarkers, and synergistic interactions between causative factors. Collectively, this review summarizes the multifaceted role of mitochondrial dysfunction in ALF/ACLF and highlights targeted strategies to interrupt the pathogenic cascade, offering potential avenues to improve patient outcomes.</p>