Decreased NAD⁺ levels have been shown to contribute to metabolic dysfunction during aging. NAD⁺ decline can be partially prevented by knockout of the enzyme CD38. However, it is not known how CD38 is regulated during aging, and how its ecto-enzymatic activity impacts NAD⁺ homeostasis. Here we show that an increase in CD38 in white adipose tissue (WAT) and the liver during aging is mediated by accumulation of CD38⁺ immune cells. Inflammation increases CD38 and decreases NAD⁺. In addition, senescent cells and their secreted signals promote accumulation of CD38⁺ cells in WAT, and ablation of senescent cells or their secretory phenotype decreases CD38, partially reversing NAD⁺ decline. Finally, blocking the ecto-enzymatic activity of CD38 can increase NAD⁺ through a nicotinamide mononucleotide (NMN)-dependent process. Our findings demonstrate that senescence-induced inflammation promotes accumulation of CD38 in immune cells that, through its ecto-enzymatic activity, decreases levels of NMN and NAD⁺.