We hypothesized that doxorubicin (DR) induced chronic kidney disease (CKD) could trigger the intrinsic and the extrinsic renal cell apoptotic pathways, while treadmill exercise could help prevent adverse effects. Male Sprague-Dawley rats were subjected to treadmill running exercise at a speed of 30 m/min, 30 or 60 min/day, 3 times per week, for a total period of 11 weeks. The physiological and biochemical parameters were seen substantially improved (DR-CKD control, 30 min, 60 min exercise): the ratio of kidney weight/body weight (0.89, 0.74, and 0.72); the WBC (1.35, 1.08, and 1.42 × 104 cells/μL); RBC (5.30, 6.38, and 6.26 × 106 cells/μL); the platelet count (15.1, 12.8, and 11.3 × 105/μL); serum cholesterol (659, 360, and 75 mg/dL); serum triglyceride (542, 263, and 211 mg/dL); BUN (37, 25, and 22 mg/dL). Bcl-2 and intramitochondrial cytochrome c were upregulated, while the levels of Bax, SOD, MDA, cleaved caspases 9, 3, 8, 12, and calpain were all downregulated in DRCKD groups with exercise. CHOP (GADD153) and GRP78 were totally unaffected. FAS (CD95) was only slightly suppressed in the 60 min exercise DRCKD group. Conclusively, exercise can ameliorate CKD through the regulation of the intrinsic and extrinsic apoptosis pathways. The 60 min exercise yields more beneficial effect than the 30 min counterpart.