Liver cancer is the third leading cause of cancer‑related mortality globally, with increasing morbidity and mortality rates. Sorafenib, a multi‑kinase inhibitor, is an effective first‑line therapy for late‑stage liver cancer. However, its effectiveness is hindered by low responsiveness, high drug resistance and significant side effects. The progression and metastasis of liver cancer are associated with alterations in mitochondrial metabolism, including mitochondrial stress responses and defects in oxidative phosphorylation, which are involved in the increased production of reactive oxygen species. Targeting mitochondrial biogenesis and bioenergetics presents a promising therapeutic strategy. Bioinformatics analysis (integrated analysis of The Cancer Genome Atlas, mitochondrial genomes, liver cancer mouse models, and bioinformatics tools) revealed that the expression of single‑stranded DNA‑binding protein 1 (SSBP1) was significantly elevated in liver cancer. In addition, MTT and colony formation assays showed that increased SSBP1 expression notably enhanced cell proliferation, while wound healing and Transwell assays demonstrated enhanced metastasis. Furthermore, flow cytometry, qPCR, and western blotting indicated that SSBP1 knockout impaired mitochondrial function and increased sensitivity to sorafenib, effectively attenuating cancer progression. Clinical correlation analysis demonstrated that higher SSBP1 expression was associated with poorer prognosis in patients with liver cancer. In summary, the present study identified SSBP1 as a potential driver of tumor growth and a promising prognostic biomarker and therapeutic target in liver cancer, thus providing novel insight for improving patient outcomes.