Nicotinamide adenine dinucleotide (NAD⁺) is a vital molecule found in all living cells. NAD⁺ intracellular levels are dictated by its synthesis, using the de novo and/or salvage pathway, and through its catabolic use as co-enzyme or co-substrate. The regulation of NAD⁺ metabolism has proven to be an adequate drug target for several diseases, including cancer, neurodegenerative or inflammatory diseases. Increasing interest has been given to NAD⁺ metabolism during innate and adaptive immune responses suggesting that its modulation could also be relevant during host–pathogen interactions. While the maintenance of NAD⁺ homeostatic levels assures an adequate environment for host cell survival and proliferation, fluctuations in NAD⁺ or biosynthetic precursors bioavailability have been described during host–pathogen interactions, which will interfere with pathogen persistence or clearance. Here, we review the double-edged sword of NAD⁺ metabolism during host–pathogen interactions emphasizing its potential for treatment of infectious diseases.