Ergothioneine emerges as a uniquely promising longevity compound through its selective tissue accumulation via the OCTN1 transporter, specifically targeting telomere maintenance, mitochondrial integrity, and NRF2-mediated cellular defense pathways. This systematic review spanning two decades reveals ergothioneine's multi-target approach to combating neurodegeneration, cardiovascular decline, and metabolic dysfunction—addressing core aging mechanisms simultaneously. The compound's designation as a potential 'longevity vitamin' reflects its ability to act beyond simple antioxidant function, modulating fundamental cellular homeostasis processes that deteriorate with age. The identification of genetic variations in SLC22A4/SLC22A15 transporters suggests personalized nutrition approaches could optimize ergothioneine's benefits, marking a shift toward precision longevity interventions. While abundant in mushrooms and certain other foods, ergothioneine's therapeutic potential remains largely untapped in clinical settings. This comprehensive analysis positions ergothioneine as one of the most scientifically compelling dietary longevity candidates, though rigorous human trials are essential to validate its geroprotective effects and establish optimal dosing strategies for healthspan extension.