Lipoic acid (LA) has been shown to possess protective effects against liver fibrosis mainly by induction of apoptosis of activated hepatic stellate cells, but the mechanism of LA activity in liver fibrosis has yet to be completely explained. LA occurs naturally in mitochondria as a coenzyme. In this study, we used mice with schistosomiasis-induced liver fibrosis and mouse hepatocarcinoma cell line 1C1C7 as models to investigate the mitochondrial mechanism of LA treatment for liver fibrosis. Western blot, real-time PCR and oxygen consumption rate (OCR) test were used. In the livers of mice with liver fibrosis, the mRNA levels of LA synthetic pathway enzymes, including MCAT, OXSM, MECR, and LIAS, were significantly reduced. Livers of mice with liver fibrosis showed degenerative signs, such as mitochondrial edema, a reduced mitochondrial crest and matrix density, or vacuolation; the activities of mitochondrial complexes I, II, IV, and V were also decreased in these livers. The expression of phosphorylation Drp1 (p-Drp1) was decreased in the livers of mice with liver fibrosis, indicating increased mitochondrial fission activity, whereas OPA1 and MFN1 expression was reduced, denoting decreased activity of mitochondrial fusion. To understand the mitochondrial mechanism of LA treatment for liver fibrosis, p-Drp1, OPA1, and MFN1 expression were detected at the protein level in mouse hepatocarcinoma cell line 1C1C7 stimulated by LA. OPA1 and MFN1 were not significantly altered, but p-Drp1 was significantly increased. The results suggest that LA may alleviate liver fibrosis through upregulating p-Drp1. This study provides a new insight into the mechanism of the protective effect of LA against schistosomiasis-induced liver fibrosis, which demonstrates that LA is required for the maintenance of mitochondrial function by upregulating p-Drp1 expression to inhibit mitochondrial fission.