Hypertension is characterized by endothelial dysfunction and arterial stiffness, which contribute to the pathogenesis of atherosclerotic cardiovascular diseases. Nicotinamide adenine dinucleotide (NAD⁺) is an indispensable cofactor in all living cells that is involved in fundamental biological processes. However, in hypertensive patients, alterations in NAD⁺ levels and their relation with blood pressure (BP) elevation and vascular damage have not yet been studied. Here we reported that hypertensive patients exhibited lower NAD⁺ levels, as detected by high-performance liquid chromatography-mass spectrometry (HPLC-MS), in both peripheral blood mononuclear cells (PBMCs) and aortas, which was parallel to vascular dysfunction. NAD⁺ boosting therapy with nicotinamide mononucleotide (NMN) supplement reduced BP and ameliorated vascular dysfunction in hypertensive patients (NCT04903210) and AngII-induced hypertensive mice. Upregulation of CD38 in endothelial cells led to endothelial NAD⁺ exhaustion by reducing NMN bioavailability. Pro-inflammatory macrophages infiltration and increase in IL-1β generation derived from pro-inflammatory macrophages resulted in higher CD38 expression by activating JAK1-STAT1 signaling pathway. CD38 KO, CD38 inhibitors treatment, or adeno-associated virus (AAV)-mediated endothelial CD38 knockdown lowered BP and improved vascular dysfunction in AngII-induced hypertensive mice. The present study demonstrated for the first time that endothelial CD38 activation and subsequently accelerated NAD⁺ degradation due to enhanced macrophage-derived IL-1β production was responsible for BP elevation and vascular damage in hypertension. NAD⁺ boosting therapy can be used as a novel therapeutic strategy for the management of hypertensive patients.