Background: Chronic kidney disease (CKD) is a gradual damage to kidneys, featured by tubular atrophy, glomerulosclerosis and interstitial fibrosis. It is associated with cognitive dysfunctions. Moreover, inflammation and oxidative stress play vital roles in pathophysiology and progression of both CKD and accompanying neurobehavioral changes. This study aimed to detect possible beneficial effects of quercetin and vitamin D on progression of CKD and its associated neurological complications and to detect their possible mechanism/s in relation to klotho gene expression in CKD rat model. Methods: Thirty adult male albino rats were allocated into 5 groups as the following: Group 1 (Control group), Group 2 (CKD group), Group 3 (CKD+ quercetin group), Group 4 (CKD+VIT D3), and Group 5 (CKD+ quercetin+ VIT D3). Kidney function tests, some inflammatory, apoptotic and oxidative stress markers, BDNF, Klotho gene expression in kidney and brain and behavioral tests were assessed for all groups. Results: There was a significant deterioration in all parameters in CKD group. However, treated groups showed a significant improvement, especially the combined treated group. These results were supported by the significant improvement in histopathological examination. Conclusion: Quercetin and vitamin D supplementation caused elevation of klotho gene expression which in turn decreases oxidative stress, fibrosis, and apoptosis. They also increase BDNF which attenuates the associated neurobehavioral complications. So, they had a prophylactic role in CKD, prevented its progression and attenuated the associated neurobehavioral complications.