Introduction: Chronic kidney disease (CKD) is characterized by fibroblast activation, myofibroblast formation, and up-regulation of transforming growth factor-β1 (TGF-β1) that may activate Snail in fibroblast to myofibroblast transition. Ethanol extract of Yacon leaves is known to have a renoprotective effect on diabetic nephropathy but its effect in the CKD model is unknown. This experimental study aimed to elucidate the effect of ethanol extract from Yacon leaves in attenuating renal failure in a CKD mice model. Methods: Male Swiss-Webster mice (3 months, 30–40 grams, n=25) underwent 5/6 subtotal nephrectomy (SN) to induce CKD. The mice were divided into five groups: SN, SN mice with oral treatment of Yacon leaves ethanol extract with doses 0.735 μg/kg (SN+YK1), 1.47 μg/kg (SN+YK2), and 2.94 μg/kg (SN+YK3), and a Sham operation (SO) group with aquadest 0.1% supplementation. Mice were euthanized on day 14 after the operation and kidneys were harvested. Paraffin sections were used for histological analysis. Immunostaining was done for quantifying fibroblasts and myofibroblasts. We performed RT-PCR to measure TGF-β1 and Snail mRNA expressions. Results: The SN group had significantly higher fibroblast number, myofibroblast fraction area, TGF-β1 and Snail mRNA expressions compared to the SO. The fibroblasts number (p<0.001) and myofibroblast fraction areas (p<0.001) were significantly lower in Yacon treated-groups compared to the SN group. RT-PCR analysis showed lower mRNA expressions of TGF-β1 and Snail, but no significant differences were found among the various Yacon treated-groups. Conclusion: Ethanol extracts of Yacon leaves improved kidney damage in male mice with 5/6 subtotal nephrectomy model.