PPARA is nuclear hormone receptor that promotes fatty acid β-oxidation (FAO) and oxidative phosphorylation (OXPHOS). We and others have recently shown that PPARA and its target genes are downregulated, and FAO and OXPHOS are impaired in autosomal dominant polycystic kidney disease (ADPKD). However, whether PPARA and FAO/OXPHOS are causally linked to ADPKD progression is not entirely clear. We report that expression of PPARA and FAO/OXPHOS genes is downregulated and in-vivo β-oxidation rate of 3H-labelled triolein is reduced in Pkd1RC/RC mice, a slowly-progressing orthologous model of ADPKD that closely mimics the human ADPKD phenotype. To evaluate the effects of upregulating PPARA, we conducted a 5-month, randomized, pre-clinical trial by treating Pkd1RC/RC mice with fenofibrate, a clinically-available PPARA agonist. Fenofibrate treatment resulted in increased expression of PPARA and FAO/OXPHOS genes, upregulation of peroxisomal and mitochondrial biogenesis markers, and higher β-oxidation rates in Pkd1RC/RC kidneys. MRI-assessed total kidney volume and total cyst volume, kidney-weight-to-body-weight ratio, cyst index, and serum creatinine levels were significantly reduced in fenofibrate-treated compared to untreated littermate Pkd1RC/RC mice. Moreover, fenofibrate treatment was associated with reduced kidney cyst proliferation and infiltration by inflammatory cells including M2-like macrophages. Finally, fenofibrate treatment also reduced bile duct cyst number, cyst proliferation, and liver inflammation and fibrosis. In conclusion, our studies suggest that promoting PPARA activity to enhance mitochondrial metabolism may be a useful therapeutic strategy for ADPKD.