Objective: To investigate the protective effects of chenodeoxycholic acid (CDCA), a potent physiological agonist of the farnesoid X receptor (FXR), on renal fibrosis in 5/6 nephrectomized (l-PNx) mice fed a high-fat diet and to explore its implications for physical resilience and recovery in chronic kidney disease (CKD). Methods: l-PNx mice were randomly assigned to high-fat or low-fat diet groups. After four weeks of dietary intervention, mice were treated with CDCA or placebo for an additional four weeks. Renal function was assessed by monitoring biochemical markers, pathological changes, and fibrosis-related factor expression. Primary mesangial cells (P-MCs) were isolated from C57/BL6 mice and exposed to exogenous TGF-β to induce fibrosis. These cells were treated with CDCA and Fxrα2 adenovirus (adv-FXRα2) to activate FXR. Biochemical, molecular, and histological analyses were performed to evaluate the effects of CDCA on renal fibrosis. Results: Mice in the high-fat diet group exhibited significantly increased body weight, deteriorated renal function, and elevated albuminuria compared to those on a low-fat diet. CDCA treatment significantly reduced levels of urea, creatinine, and urinary protein, with the most pronounced effects observed in high-fat diet-fed mice. Mechanistically, CDCA downregulated the expression of fibrotic markers and Smad3 in kidney tissues, while upregulating Smad7 expression. Similar results were observed in TGF-β-induced P-MCs following CDCA and adv-FXRα2 treatment, confirming the role of FXR activation in mitigating fibrosis. Conclusion: CDCA protects against renal fibrosis by modulating the TGF-β/Smad signaling pathway, reducing Smad3 expression and increasing Smad7 expression, thereby delaying the progression of chronic kidney disease. These findings highlight the potential of FXR agonists like CDCA as therapeutic options for obesity-associated CKD. By improving renal function and reducing fibrosis, CDCA may enhance physical resilience and recovery, supporting its integration into multidisciplinary approaches for managing CKD, particularly in populations where physical performance and rehabilitation are critical.