Chronic kidney disease (CKD) is a global health concern characterized by the presence of irreversible kidney damage. The renoprotective role of adipose mesenchymal stromal cell-derived exosomes (ADMSCs-Exos) and roflumilast (ROF) in the management of acute kidney damage has been demonstrated in preclinical studies. Objectives: The current study was conducted to investigate the potential therapeutic efficacy of Exos combined with ROF in the management of CKD. Material and methods: Isolating and characterizing exosomes involved using electron microscopy and flow cytometry techniques. Rats were randomly separated into seven groups, Control group: rats were injected with 0.9% saline. ROF group: The rats received an oral administration of ROF at a dosage of 1.2 mg/kg. Exos group: rats were given two injections of 100 μg Exos. DOX group: rats were subjected to two injections on day 1 and day 14, at a dosage of 4 mg/kg of DOX. DOX + ROF group: rats were administered ROF for a duration of 7 days following each injection of DOX. DOX + Exos group: rats were administered exosomes five days after receiving both doses of DOX. DOX + ROF+ Exos group: rats were administered both ROF and Exos subsequent to each DOX injection. At the end of the experiment, kidney functions, antioxidant status and renal histology was detected. Results: The isolated exosomes exhibited the characteristic cup-shaped morphology and expressed the surface proteins CD81, CD9, and CD63. The administration of ROF or Exos resulted in a notable enhancement in both renal functions and structural integrity when compared to the DOX group (p < 0.05). Furthermore, the administration of ROF or Exos resulted in an increase in the levels of the antioxidant GSH, while the level of MDA was shown to decrease compared to the DOX group (p < 0.05) with the combination group showing the most significant improvement. Conclusion: The study findings demonstrate for the initial instance that the administration of ROF and Exos may confer protection against DOX-induced CKD by ameliorating both renal function and morphology.