As the global population ages, the prevalence of cognitive decline is rising, creating urgent demand for proactive strategies that support brain health and healthy aging. Ergothioneine, a unique dietary amino-thione absorbed via the OCTN1 transporter, has recently gained attention for its potential as a neuroprotective, longevity-promoting compound. This review synthesizes growing evidence from observational, interventional, and mechanistic studies. Observational data consistently associate low blood ergothioneine levels with cognitive impairment, neurodegenerative diseases, cardiovascular disorders, frailty, and mortality. Interventional trials in older adults suggest that ergothioneine supplementation may improve cognition, memory, sleep quality, and stabilize neurodegeneration biomarkers, with no safety concerns at doses up to 25 mg/day. Mechanistic studies reveal that ergothioneine acts through multiple pathways: mitigating oxidative stress, reducing neuroinflammation, preserving mitochondrial function, and potentially modulating neurogenesis and NAD⁺ metabolism, although some mechanisms require further investigation. Beyond cognition, ergothioneine shows promise in supporting other physiological systems relevant to aging, including cardiovascular, metabolic, gut, eye, auditory, liver, kidney, immune, skin, and lung health. Together, current evidence positions ergothioneine as a promising nutritional intervention for promoting cognitive resilience and systemic health in aging, although larger, long-term interventional trials are needed to confirm causality and optimize use.