Chronic kidney disease (CKD), particularly the end-stage renal disease (ESRD), is commonly associated with dysfunction of Klotho-FGF23 axis. Aortic stiffness represents one of the most prevalent vascular abnormalities significantly influencing the prognosis of dialysis patients, and is an independent factor for predicting risks of cardiovascular events and mortality. Recent studies have indicated that aortic stiffness indicates the presence of cardiovascular abnormalities, and triggers cerebral microvascular injury and cognitive decline by transmission of the excessive vascular pulse to brain microcirculation. Consequently, aortic stiffness is regarded as a key hemodynamic chain linking ‘cardio-renal-cerebral’ injury. Klotho-FGF23 axis is a core regulatory system relating to CKD-mineral and bone disorder (CKD-MBD). Dysfunction of the axis promotes vascular calcification, inflammation, oxidative stress, and endothelial impairment to accelerate aortic stiffness, which contributes to cerebral microvascular injury and dysfunction of neuro-vascular unit to produce cognitive decline. This paper introduces the ‘Klotho-FGF23 axis dysfunction - aortic stiffness - cerebral microcirculatory impairment - cognitive decline’ pathological pathway to review its mechanism and recent research advances and to construct a ‘heart-kidney-brain’ sequential injury model in dialysis patients, in order to provide theoretical bases for comprehensive management of the injuries.