Mitochondrial dynamics imbalance denotes the disruption of the homeostatic balance between mitochondrial fission and fusion under physiological or pathophysiological conditions, typically manifested as enhanced fission or impaired fusion, leading to abnormalities in mitochondrial quantity, morphology, and function. Characterized primarily by mitochondrial fragmentation, this phenomenon has been extensively documented in various cancers. As a highly metabolic organ rich in mitochondria, the liver is particularly susceptible to such imbalance, which plays a critical role in hepatocellular carcinoma (HCC) initiation, progression, and therapy resistance. This review systematically summarizes the molecular mechanisms underlying mitochondrial dynamics imbalance in HCC and evaluates its clinical potential in diagnosis, treatment, and prognosis. We first outline the core regulatory network, covering fission-related proteins (e.g., DRP1, FIS1, MFF, MIEF1/2), fusion-related proteins (e.g., OPA1, MFN1/2), and upstream regulators (e.g., miR-761, GNPAT, HBV). We then discuss its emerging role as a biomarker for early detection, risk stratification, and outcome prediction in HCC. Furthermore, we analyze how this imbalance contributes to resistance against chemotherapy, targeted therapy, and immunotherapy, along with relevant intervention strategies. Additionally, we review its impact on the tumor microenvironment via immunomodulation and its clinical implications in promoting HCC metastasis. Finally, we highlight the translational significance of mitochondrial dynamics research in HCC precision medicine, address current challenges in clinical application, and propose future directions that integrate mechanistic insights, technological advances, and rigorous clinical validation to advance toward personalized therapeutic approaches.