<p>Axons are metabolically active neuronal segments with well-controlled axonal degeneration and regeneration. External stress or injury displaces this equilibrium toward degeneration leading to axonal dysfunction observed in the pathology of several diseases. The demand and supply matrix of energy at the synapses are maintained by the axonal transport. Nicotinamide adenine dinucleotide (NAD⁺) is a major energy-driving coenzyme of cells that controls mitochondrial, cytoplasmic, and other organellar energy cycles generating high amounts of adenosine triphosphate (ATP). NAD⁺ participates in various cellular cycles and is consumed by several enzymes. One of the key enzymes targeting NAD⁺ is Sterile alpha and TIR motif-containing protein 1 (SARM1) which gets activated in response to external noxious stimuli. SARM1 is an octamer consisting of multiple domains of which the TIR domain governs NAD⁺ hydrolysis which eventually leads to axonal deficits. Besides its localization in neurons, SARM1 is also present in astrocytes, microglia, and macrophages in which it regulates inflammatory responses associated with disease pathology. SARM1 localization in the outer mitochondrial membrane is responsible for its association with mitochondrial dynamics. SARM1-mediated mitochondrial dysfunction further drives the axonal degeneration associated with peripheral and central nervous system disorders. Several genetic and pharmacological studies highlight the role of SARM1 in axonal degeneration. SARM1 is thus becoming a popular target for preventing axonal degeneration. Several small molecules consisting of isoquinoline, isothiazole, pyridine, and tryptoline acrylamide moieties have been tested for their activity against SARM1 with a promising foundation for drug discovery in targeting SARM1. In our review, we highlight the role of SARM1 in axonal degeneration associated with several disease pathologies focusing on genetic and pharmacological evaluation.</p>