Nicotinamide adenine dinucleotide (NAD) and its reduced form NADH are essential cofactors for many redox biocatalysts. Because these cofactors are consumed in stoichiometric amounts, whole–cell biocatalysts have been routinely employed in order to reduce the costs. To further improve the efficacy of redox biocatalysts, it is essential to maintain the stability of nicotinamide cofactors, for which it is attractive to block degradation pathways for NAD(H). While the biosynthesis of NAD(H) has been well studied, it is less understood how NAD(H) are degraded. Here we demonstrated that UshA was a major periplasmic enzyme for NAD degradation in Escherichia coli. Purified recombinant UshA showed high pyrophosphatase activity with the catalytic efficiencies for hydrolysis of NAD and NADH at 3.7 μM−1 s−1 and 1.4 μM−1 s−1, respectively. Deletion of the ushA gene from the chromosome led to faster cell growth and improved extracellular NAD stability by 3–fold under conditions similar to whole–cell biocatalysis. These results significantly enriched our understanding on NAD metabolism, and should facilitate many applications including designing more robust redox biocatalysts.