Nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) is an evolutionarily conserved nicotinamide adenine dinucleotide (NAD⁺) synthase located in the cytoplasm and Golgi apparatus. NMNAT2 has an important role in neurodegenerative diseases, malignant tumors, and other diseases that seriously endanger human health. NMNAT2 exerts a neuroprotective function through its NAD synthase activity and chaperone function. Among them, the NMNAT2-NAD⁺-Sterile alpha and Toll/interleukin-1 receptor motif-containing 1 (SARM1) axis is closely related to Wallerian degeneration. Physical injury or pathological stimulation will cause a decrease in NMNAT2, which activates SARM1, leading to axonal degeneration and the occurrence of amyotrophic lateral sclerosis (ALS), Alzheimer's disease, peripheral neuropathy, and other neurodegenerative diseases. In addition, NMNAT2 exerts a cancer-promoting role in solid tumors, including colorectal cancer, lung cancer, ovarian cancer, and glioma, and is closely related to tumor occurrence and development. This paper reviews the chromosomal and subcellular localization of NMNAT2 and its basic biological functions. We also summarize the NMNAT2-related signal transduction pathway and the role of NMNAT2 in diseases. We aimed to provide a new perspective to comprehensively understand the relationship between NMNAT2 and its associated diseases.