Liver fibrosis is a common complication of T2DM(Type 2 diabetes mellitus). Appropriate intervention (exercise or drugs) in the early stage of liver fibrosis can slow down or even reverse liver fibrosis. MOTS-c (Mitochondrial open reading frame of the 12 S r RNA type-c ) has been described as an exercise-mimicking substance, and its effects are similar to those achieved by aerobic exercise; however, the exact mechanism remains to be elucidated. In this study, liver function was impaired in a T2DM rat model, leading to the aggravation of liver fibrosis. T2DM rats with liver fibrosis were subjected to MOTS-c, aerobic exercise therapy, or their combination. HE staining, Masson's trichrome staining and immunohistochemistry were used for histopathological examination. Transcriptome sequencing, q-PCR and WB were used to detect the expression of Keap1 (Kelch-like ECH-associated protein 1), Nrf2 (Nuclear factor erythroid 2-related factor 2 ), Smad2/3/4 and other genes. MOTS-c and aerobic exercise therapy improved T2DM-induced liver fibrosis. Additionally, cells were transfected with MOTS-c overexpression or interference plasmids or MOTS-c was added to the culture medium. MOTS-c overexpression or MOTS-c addition to the culture medium inhibited ROS levels, increased the mRNA and protein expression of Keap1-Nrf2 pathway genes and decreased the expression of TGF-β1(Transforming growth factor-beta1)/Smad pathway genes. Our findings demonstrate that MOTS-c modulates the progression of T2DM complicated by liver fibrosis through a Keap1-Nrf2-Smad2/3 signaling pathway-dependent mechanism.